naphthoquinones and Neoplasms

Nanotechnology shows the power to improve efficacy and reduce the adverse effects of anticancer agents. As a quinone-containing compound, beta-lapachone (LAP) is widely employed for targeted anticancer therapy under hypoxia. The principal mechanism of LAP-mediated cytotoxicity is believed due to the continuous generation of reactive oxygen species with the aid of NAD(P)H: quinone oxidoreductase 1 (NQO1). The cancer selectivity of LAP relies on the difference between NQO1 expression in tumors and that in healthy organs. Despite this, the clinical translation of LAP faces the problem of narrow therapeutic window that is challenging for dose regimen design. Herein, the multifaceted anticancer mechanism of LAP is briefly introduced, the advance of nanocarriers for LAP delivery is reviewed, and the combinational delivery approaches to enhance LAP potency in recent years are summarized. The mechanisms by which nanosystems boost LAP efficacy, including tumor targeting, cellular uptake enhancement, controlled cargo release, enhanced Fenton or Fenton-like reaction, and multidrug synergism, are also presented. The problems of LAP anticancer nanomedicines and the prospective solutions are discussed. The current review may help to unlock the potential of cancer-specific LAP therapy and speed up its clinical translation.

Topics: Antineoplastic Agents; Cell Line, Tumor; NAD(P)H Dehydrogenase (Quinone); Nanomedicine; Naphthoquinones; Neoplasms; Prospective Studies

Napabucasin (also known as BBI608) is a natural naphthoquinone originally identified as a cancer cell stemness inhibitor. Accumulated in vitro and in vivo evidence demonstrated that napabucasin showed significant anticancer effects in various types of cancers. Napabucasin inhibits cancer cell proliferation, induces apoptosis and cell cycle arrest, and suppresses metastasis and relapse. Such anticancer activities of napabucasin mainly rely on the inhibition of cancer stemness by targeting signal transducer and activator of transcription 3 (STAT3) and its related gene inhibition. However, several novel molecular targets for napabucasin, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and thioredoxin reductase 1 (TrxR1), have been reported. Napabucasin represents a promising anticancer lead for multiple cancers. In this mini review, the anticancer potential and the molecular mechanism of napabucasin will be briefly highlighted.

Topics: Apoptosis; Benzofurans; Cell Line, Tumor; Humans; Naphthoquinones; Neoplasms; STAT3 Transcription Factor

In recent years, many naphthoquinone compounds with anticancer activity have been identified in Arnebiae Radix, and some of them have the potential to be developed into anticancer drugs.. This article aimed to provide a comprehensive overview of the anticancer effects of naphthoquinone compounds through a detailed review of literature and Chinese patents, and discuss their potential to be developed as anticancer drugs for clinical application.. Research papers were collected through the databases of PubMed, Cnki and SciDirect using keyword searches "naphthoquinone compounds" and "anticancer". The keywords of "shikonin" and "shikonin derivatives" were also used in PubMed, Cnki and SciDirect databases to collect research articles. The Chinese patents were collected using the Cnki patent database.. Naphthoquinone compounds have been found to possess anti-cancer activity, and their modes of action are associated with inducing apoptosis, inhibiting cancer cell proliferation, promoting autophagy in cancer cells, anti-cancer angiogenesis and inhibition of cell adhesion, invasion and metastasis, inhibiting glycolysis and inhibiting DNA topoisomerase activity.. Most of the naphthoquinone compounds show effective anti-cancer activity in vitro. The structure modification of naphthoquinone aims to develop anti-cancer drugs with high efficacy and low toxicity.

Topics: Antineoplastic Agents; Cell Proliferation; Humans; Naphthoquinones; Neoplasms; Patents as Topic

Plumbagin has gained a lot of attention in research due to its various therapeutic actions. It is a secondary metabolite obtained from different plant families, such as Plumbaginaceae, Droseraceae, and Ebenceae. Various studies on plumbagin have revealed that it is a natural gift for mankind in treating chronic diseases, like cancer, diabetes, malaria, bacterial infection, and controlling cardiovascular disease. However, there are several challenges in developing plumbagin as a therapeutic agent. The first and foremost is its limited solubility and oral bioavailability. The second limitation is its toxicity. Plumbagin has a narrow therapeutic window, and literature reveals that the compound has moderate toxicity in animals. However, data are insufficient to prove that plumbagin is unsafe for humans. Despite the many therapeutic benefits of plumbagin, it remains unexploited for mankind. Thus, a systematic review of its toxicity, pharmacology, and safety is required to be performed. This review work signifies the depth of therapeutic applications proven via research, its different modes of isolation and separation of chemical constituents, and its modification. A thorough review of promising therapeutic targets via docking studies is also presented. Different methods used to quantify plumbagin from the plant are reviewed. An overview of attempts to design novel formulations which could enhance its bioavailability is also presented. The review paper will help the scientist to exploit the drug to its optimum, which will help to overcome the challenges faced during its design and developmental stages.

Topics: Animals; Humans; Naphthoquinones; Neoplasms; Plumbaginaceae; Research

Juglone (5 - hydroxy - 1, 4 - naphthalene diketone) is a kind of natural naphthoquinone, present in the roots, leaves, nut-hulls, bark and wood of walnut trees. Recent studies have found that Juglone has special significance in the treatment of cancer, which plays a significant role in the resistance of cancer cell proliferation, induction of cancer cell apoptosis, induction of autophagy, anti-angiogenesis and inhibition of cancer cell migration and invasion, etc. Additionally, its derivatives also play a tumor suppressive effect. In conclusion, Juglone and its derivatives have been identified as effective anticancer drugs. This paper reviews action mechanisms of Juglone and its derivatives in cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Movement; Cell Proliferation; DNA-Directed DNA Polymerase; Humans; Naphthoquinones; Neoplasms; Neovascularization, Pathologic; NIMA-Interacting Peptidylprolyl Isomerase; Reactive Oxygen Species

Shikonin and its enantiomeric analogue, alkaninn, are prevailing natural lead compounds in the drug discovery and development of anticancer agents. Despite having numerous biological effects, the most important activity reported for shikonin derivatives is the antitumor effect which is exerted through various mechanisms such as induction of apoptosis and autophagy. The design, synthesis, and development of new shikonin derivatives are continuously performed with the aim of promoting therapeutic effects through increasing cytotoxicity against cancer cells and simultaneously reducing toxicity on normal cells. In spite of significant advances in the development of shikonin derivatives in recent years and the publication of some reviews in this regard, the structural classification, synthesis methods, as well as the diversity of the anti-tumor mechanism of action of these compounds have not been well considered. This review aims to provide comprehensive data in this regard by reviewing studies conducted over the last two decades (from 2000 until now).

Topics: Antineoplastic Agents; Apoptosis; Humans; Naphthoquinones; Neoplasms

β-Lapachone (β-lap, 1), an ortho-naphthoquinone natural product isolated from the lapacho tree (Tabebuia avellanedae) in many regions of South America, has received extensive attention due to various pharmacological activities, such as antitumor, anti-Trypanosoma cruzi, anti-Mycobacterium tuberculosis, antibacterial, and antimalarial activities. Related mechanisms of β-lap have been widely investigated for a full understanding of its therapeutic potentials. Numerous derivatives of β-lap have been reported with aims to generate new chemical entities, improve the corresponding biological potency, and overcome disadvantages of its physical and chemical properties and safety profiles. This review will give insight into the pharmacological mechanisms of β-lap and provide a comprehensive understanding of its structural modifications with regard to different therapeutic potentials. The available clinical trials related to β-lap and its derivatives are also summarized.

Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Drug Discovery; Humans; Naphthoquinones; Neoplasms; Tabebuia

Cancer is a deadly disease, which has significantly increased in both developed and developing nations. Treatment of cancer utilizing radiotherapy or chemotherapy actuates a few issues which incorporate spewing, sickness, unpalatable reactions, and so forth. In this specific situation, an alternative drug source, which can effectively treat cancer is of prime importance. Products that are obtained from plant sources are utilized for the treatment of various diseases due to their non-harmful nature. Medicinal plants contain different bioactive compounds, which possess an important role in the prevention of different diseases such as cancer. Plumbagin is a bioactive compound, which is mainly present in Plumbaginaceae family and has been explored for its anticancer activity. Plumbagin basically inactivates the Akt/NF-kB, MMP-9 and VEGF pathways that are essential for cancer cell development. Therefore, it is important to review the role of plumbagin in different cancer cells in order to find an alternative drug to overcome this disease. The present review provides a summary of anticancer activity of plumbagin in various cancers and its mode of action.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Humans; Naphthoquinones; Neoplasms; NF-kappa B; Plumbaginaceae; Signal Transduction

This review aims to explore the potential of resveratrol, a polyphenol stilbene, and beta-lapachone, a naphthoquinone, as well as their derivatives, in the development of new drug candidates for cancer. A brief history of these compounds is reviewed along with their potential effects and mechanisms of action and the most recent attempts to improve their bioavailability and potency against different types of cancer.

Topics: Antineoplastic Agents; Humans; Inhibitory Concentration 50; Naphthoquinones; Neoplasms; Resveratrol; Tumor Suppressor Protein p53

Mitochondria are considered one of the most important subcellular organelles for targeting and delivering drugs because mitochondria are the main location for various cellular functions and energy (i.e., ATP) production, and mitochondrial dysfunctions and malfunctions cause diverse diseases such as neurodegenerative disorders, cardiovascular disorders, metabolic disorders, and cancers. In particular, unique mitochondrial characteristics (e.g., negatively polarized membrane potential, alkaline pH, high reactive oxygen species level, high glutathione level, high temperature, and paradoxical mitochondrial dynamics) in pathological cancers have been used as targets, signals, triggers, or driving forces for specific sensing/diagnosing/imaging of characteristic changes in mitochondria, targeted drug delivery on mitochondria, targeted drug delivery/accumulation into mitochondria, or stimuli-triggered drug release in mitochondria. In this review, we describe the distinctive structures, functions, and physiological properties of cancer mitochondria and discuss recent technologies of mitochondria-specific "key characteristic" sensing systems, mitochondria-targeted "drug delivery" systems, and mitochondrial stimuli-specific "drug release" systems as well as their strengths and weaknesses.

Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Glutathione; Guanidine; Humans; Hydrogen-Ion Concentration; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Dynamics; Molecular Targeted Therapy; Naphthoquinones; Neoplasms; Peptides; Reactive Oxygen Species; Rhodamines; Temperature

The jadomycins are an expanding class of compounds produced from Streptomyces venezuelae, by diverting the normal biosynthesis which provides the antibiotic chloramphenicol. In the presence of amino acids, and either by heat shock, supplementation with ethanol, or when phage SV1 is added to the culture, the formation of substituted jadomycins and benzo[b]phenanthridines can be achieved. The first part of this review provides details of intermediates involved in the biosynthesis of the jadomycins and the related benzo[b]phenanthridines. Both the jadomycins and the benzo[b]phenanthridines share biosynthetic pathways with a large class of naturally occurring compounds known as the angucyclines. The biosynthetic pathways diverge when it is postulated that an intermediate quinone, such as 3-(2-formyl-6-hydroxy-4-methylphenyl)-8-hydroxy-1,4-naphthoquinone-2-carboxylic acid is formed. The quinone then undergoes reactions with amino acids and derivatives in the culture medium to ultimately afford a library of jadomycins and a few benzo[b]phenanthridines. The second part of the review initially details synthetic efforts toward the synthesis of the naturally occurring benzo[b]phenanthridine, phenanthroviridin, and then outlines methods that have been used to assemble a selection of jadomycins. Total syntheses of jadomycin A and B, derived from l-isoleucine, are described. In addition, the synthesis of the aglycon of jadomycins M, W, S, and T is outlined. These four jadomycins were derived from l-methionine, l-tryptophan, l-serine and l-threonine respectively. As a result of these synthetic efforts, the structures of jadomycin S and T have been revised. The third part of the review describes the reported antibacterial and anticancer activities of both the jadomycins and some naturally occurring benzo[b]phenanthridines.

Topics: Alkaloids; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Bacteria; Candida albicans; Humans; Isoquinolines; Naphthoquinones; Neoplasms; Phenanthridines

Naturally occurring naphthoquinones (NQs) comprising highly reactive small molecules are the subject of increasing attention due to their promising biological activities such as antioxidant, antimicrobial, apoptosis-inducing activities, and especially anticancer activity. Lapachol, lapachone, and napabucasin belong to the NQs and are in phase II clinical trials for the treatment of many cancers. This review aims to provide a comprehensive and updated overview on the biological activities of several new NQs isolated from different species of plants reported from January 2013 to January 2020, their potential therapeutic applications and their clinical significance.

Topics: Anti-Infective Agents; Apoptosis; Drug Screening Assays, Antitumor; Fungi; Humans; Naphthoquinones; Neoplasms; Plants; Structure-Activity Relationship

Plumbagin (PLB), a natural naphthoquinone constituent isolated from the roots of the medicinal plant

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Damage; Drug Screening Assays, Antitumor; Glutathione; Humans; Inhibitory Concentration 50; Liposomes; Mice; Mice, Inbred C57BL; Naphthoquinones; Neoplasm Metastasis; Neoplasms; Oxidants; Oxygen; Plant Extracts; Plants, Medicinal; Proteasome Inhibitors; Reactive Oxygen Species; Superoxides

Pyruvate kinase M2 is a critical enzyme that regulates cell metabolism and growth under different physiological conditions. In its metabolic role, pyruvate kinase M2 catalyzes the last glycolytic step which converts phosphoenolpyruvate to pyruvate with the generation of ATP. Beyond this metabolic role in glycolysis, PKM2 regulates gene expression in the nucleus, phosphorylates several essential proteins that regulate major cell signaling pathways, and contribute to the redox homeostasis of cancer cells. The expression of PKM2 has been demonstrated to be significantly elevated in several types of cancer, and the overall inflammatory response. The unusual pattern of PKM2 expression inspired scientists to investigate the unrevealed functions of PKM2 and the therapeutic potential of targeting PKM2 in cancer and other disorders. Therefore, the purpose of this review is to discuss the mechanistic and therapeutic potential of targeting PKM2 with the focus on cancer metabolism, redox homeostasis, inflammation, and metabolic disorders. This review highlights and provides insight into the metabolic and non-metabolic functions of PKM2 and its relevant association with health and disease.

Topics: Adenosine Triphosphate; Atherosclerosis; Carrier Proteins; Cell Proliferation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Glycolysis; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Insulin; Kidney Diseases; Liver; Membrane Proteins; Metabolic Diseases; Naphthoquinones; Neoplasm Metastasis; Neoplasms; Neuralgia; Oxidants; Oxidation-Reduction; Protein Isoforms; Sepsis; Signal Transduction; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Tissue Distribution

Shikonin is the major bioactive component extracted from the roots of Lithospermum erythrorhizon which is also known as "Zicao" in Traditional Chinese Medicine (TCM). Recent studies have shown that shikonin demonstrates various bioactivities related to the treatment of cancer, inflammation, and wound healing. This review aimed to provide an updated summary of recent studies on shikonin. Firstly, many studies have demonstrated that shikonin exerts strong anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis. Shikonin also triggers Reactive Oxygen Species (ROS) generation, suppressing exosome release, and activate anti-tumor immunity in multiple molecular mechanisms. Examples of these effects include modulating the PI3K/AKT/mTOR and MAPKs signaling; inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK; and regulating the expression of ERP57, MMPs, ATF2, C-MYC, miR-128, and GRP78 (Bip). Next, the anti-inflammatory and wound-healing properties of shikonin were also reviewed. Furthermore, several studies focusing on shikonin derivatives were reviewed, and these showed that, with modification to the naphthazarin ring or side chain, some shikonin derivatives display stronger anticancer activity and lower toxicity than shikonin itself. Our findings suggest that shikonin and its derivatives could serve as potential novel drug for the treatment of cancer and inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Endoplasmic Reticulum Chaperone BiP; Humans; Lithospermum; Naphthoquinones; Neoplasms; Wound Healing

Plumbagin is a naphthoquinone derived yellow crystalline phytochemical. Plumbagin has a wide range of biological effects including cytotoxicity against cancer cells both in vitro and in vivo. Due to the pleiotropic nature of plumbagin, it shows the anticancer effect by targeting several molecular mechanisms including apoptosis and autophagic pathways, cell cycle arrest, anti-angiogenic pathways, anti-invasion and anti-metastasis pathways. Among many signaling pathways the key regulatory genes regulated by plumbagin are NF-kβ, STAT3, and AKT, etc. Plumbagin is also a potent inducer of ROS, suppressor of cellular glutathione, and causes DNA strand break by oxidative DNA base damages. In vivo studies suggested that plumbagin significantly reduces the tumor weight and volume in dose-dependent manner without any side effects in tested model organisms. Another exciting aspect of plumbagin is the ability to re-sensitize the chemo and radioresistant cancer cells when used in combination or alone. Nano encapsulation of plumbagin overcomes the poor water solubility and bioavailability obstacles, enhancing the pharmaceutical relevance with better therapeutic efficacy. Moreover, plumbagin can be introduced as a future phytotherapeutic anticancer drug after fully satisfied preclinical and clinical trials.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Humans; Male; Naphthoquinones; Neoplasms; Reactive Oxygen Species; Signal Transduction

Phytochemicals gained considerable interest during the past years as source to develop new treatment options for chemoprevention and cancer therapy. Motivated by the fact that a majority of established anticancer drugs are derived in one way or another from natural resources, we focused on shikonin, a naphthoquinone with high potentials to be further developed as preventive or therapeutic drug to fight cancer. Shikonin is the major chemical component of Lithospermum erythrorhizon (Purple Cromwell) roots. Traditionally, the root extract has been applied to cure dermatitis, burns, and wounds. Over the past three decades, the anti-inflammatory and anticancer effects of root extracts, isolated shikonin as well as semi-synthetic and synthetic derivatives and nanoformulations have been described. In vitro and in vivo experiments were conducted to understand the effect of shikonin at cellular and molecular levels. Preliminary clinical trials indicate the potential of shikonin for translation into clinical oncology. Shikonin exerts additive and synergistic interactions in combination with established chemotherapeutics, immunotherapeutic approaches, radiotherapy and other treatment modalities, which further underscores the potential of this phytochemical to be integrated into standard treatment regimens.

Topics: Animals; Antineoplastic Agents, Phytogenic; Drugs, Chinese Herbal; Humans; Models, Molecular; Naphthoquinones; Neoplasms; Structure-Activity Relationship

Cancer is a leading cause of mortality in the world and metastasis is to blame. A number of naphthoquinones (NQs) have shown ability to reduce cancer stemness and metastatic potential. Furano-naphthoquinones (FNQs), which is a class of NQ characterized by the incorporation of an additional furan ring, have demonstrated improved anti-cancer potency as compared to the other classes of NQs.. In this study, the natural origins, synthetic routes and derivatives of migrastatic NQs were reviewed. The anti-invasive and anti-metastatic mechanisms of NQs and the more powerful FNQs in targeting cancer were also discussed.. The articles related to the anti-invasive mechanisms of NQs were comprehensively reviewed. The plant origins, synthetic routes and antitumor effects of more than 360 FNQs were also covered and presented according to their chemical structures.. Anti-cancer NQs inhibit cancer invasion by acting on epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and signal transducer and activator of transcription 3 (STAT3) signaling. BBI608, a natural FNQ, has entered phases I and II clinical trials. It has been regarded as a potential candidate for new-generation lead compound acting directly on CSCs to overcome the problem of chemotherapy resistance. Apart from the plant-derived FNQs, there are a number of synthetic FNQs that were found to intervene in cancer invasion and metastasis.. The anti-invasive mechanisms of NQs have been thoroughly studied. FNQs generally show higher anti-cancer activity than that of NQs. The mechanisms of action of FNQs are worth further investigation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Furans; Humans; Mice; Naphthoquinones; Neoplasms; Neoplastic Stem Cells

Naturally occurring naphthoquinones, usually in forms of botanical extracts, have been implicated with human life since ancient time, far earlier than their isolation and identification in modern era. The long use history of naphthoquinones has witnessed their functional shift from the original purposes as dyes and ornaments toward medicinal benefits. Hitherto, numerous studies have been carried out to elucidate the pharmacological profile of both natural and artificial naphthoquinones. A number of entities have been identified with promising therapeutic potential. Apart from the traditional effects of wound healing, anti-inflammatory, hemostatic, antifertility, insecticidal and antimicrobial, etc., the anticancer potential of naphthoquinones either in combination with other treatment approaches or on their own is being more and more realized. The molecular mechanisms of naphthoquinones in cells mainly fall into two categories as inducing oxidant stress by ROS (reactive oxygen species) generation and directly interacting with traditional therapeutic targets in a non-oxidant mechanism. Based on this knowledge, optimized agents with naphthoquinones scaffold have been acquired and further tested. Hereby, we summarize the explored biological mechanisms of naphthoquinones in cells and review the application perspective of promising naphthoquinones in cancer therapies.

Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Naphthoquinones; Neoplasms; Oxidative Stress; Reactive Oxygen Species

Shikonin, alkannin and their derivatives, the main ingredient of Lithospermum erythrorhizon and Arnebia euchroma (Royle) Johnst native to Inner Mongolian and Northwest of China respectively, hold promising potentials for antitumor effects via multiple-target mechanisms. This review will emphasize the importance of their antitumor activity in apoptosis, necroptosis and immunogenic cell death, and expound the relationship of their antitumor activity and naphthoquinone scaffold that could generate ROS and alkylating agent. Meanwhile, the antitumor mechanisms of naturally-occurring shikonin, alkannin and their derivatives, which were divided into the direct interaction involved in alkylating agent, covalently binding the DNA and protein, as well as the indirect interaction mediated by ROS, nonspecifically influencing the mitochondria or multiple signal pathways, will be systematically summarized and discussed.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Death; Drug Screening Assays, Antitumor; Humans; Lithospermum; Naphthoquinones; Neoplasms; Reactive Oxygen Species

It has been shown that plumbagin, a bioactive naphthoquinone isolated from three major plant families viz. Plumbaginaceae, Ebenceae and Droseraceae, definitively exhibits anticancer potential in diverse cancer cells both in vitro and in vivo. Plumbagin shows antineoplastic effects via multi-channel molecular mechanisms, including the induction of apoptosis and autophagy, the disruption of the cell cycle, the inhibition of invasion and metastasis, and anti-angiogenesis. Plumbagin inhibits the growth of cancer cells mainly through the modulation of the signals of PI3K/Akt/mTOR, AMPK, Ras, and so on. The pharmaceutical applications of plumbagin combined with nanocarriers to achieve better therapeutic efficiency are discussed in this review Among them, liposomes, nanoparticles, microspheres, micelles, and nisosomes are used in cancer treatment. The anticancer study of plumbagin in vivo is also summarized in this review. On the whole, we aim to review the research progress of plumbagin both in pharmacological and pharmaceutical filed, which may provide some reference for further research of plumbagin.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Droseraceae; Ebenaceae; Genes, ras; Humans; In Vitro Techniques; Mice; Naphthoquinones; Neoplasms; Phosphatidylinositol 3-Kinase; Phytotherapy; Plumbaginaceae; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Napabucasin (BBI608) is an orally administered small molecule that blocks stem cell activity in cancer cells by targeting the signal transducer and activator of transcription 3 pathway. The signal transducer and activator of transcription 3 pathway is over-activated in many types of cancer and has been shown to be an important pathway in cancer stem cell-mediated propagation of cancer. Cancer stem cells are a subpopulation of cancer cells considered to be the primary source of tumor growth, metastasis, and resistance to conventional therapies, and thus, responsible for cancer relapse. This review describes the clinical development program of this first-in-class cancer stemness inhibitor, including preclinical discovery, early clinical trials, current phase III clinical trial evaluation, and future therapeutic combinations. The therapeutic potential of napabucasin was first reported in a preclinical study that demonstrated the potent anti-tumor and anti-metastatic activity of napabucasin in several different cancer types, both in vitro and in vivo. In mouse models, napabucasin was effective both as a monotherapy and in combination with other agents; in particular, synergy was observed with paclitaxel in vivo. Napabucasin clinical trials have demonstrated encouraging anti-tumor activity as monotherapy and in combination with conventional therapeutics, with no significant pharmacokinetic interactions when used in combination therapies. Adverse events attributed to napabucasin have been predominantly mild, although some patients have experienced grade 3 gastrointestinal adverse events. More severe adverse events required reduced or discontinued dosing of napabucasin or medication to reverse or manage symptoms. In conclusion, napabucasin may prove useful in targeting cancer stem cells, with the potential to suppress metastasis and prevent relapse in patients with varying cancer types.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Clinical Trials as Topic; Disease Models, Animal; Humans; Naphthoquinones; Neoplasms; Neoplastic Stem Cells; STAT3 Transcription Factor

Lapachol (1), β-lapachone (2) and α-lapachone (3) are three well-studied natural products isolated from Tabebuia impetiginosa having most interesting chemodiversity and demonstrating diverse biological effects. Areas covered: The current review summarizes the recent and past discovery of chemotherapeutic agents based on the compounds 1-3. This review presents an overview of patents filed over the past two decades (1997 to 2016) mostly relating to the anticancer effects of these lapachol and lapachone analogues. Expert opinion: The large number of interesting patents published on the therapeutic potential of quinones 1-3 and their synthetic derivatives lends credence to the importance of these molecules. Moreover, these quinones demonstrated potent anticancer effects towards various cancer cell lines and chemical modification of these quinones have led to products displaying enhanced anticancer effects. It is noteworthy that the majority of patents published are on the anticancer effects of quinones 1-3 and their synthetic derivatives along with a limited number of additional biological effects. It is our opinion that in order to get lead compounds, there needs to be a greater focus on the elucidation of the precise mechanism of action of these compounds including SAR and in vivo studies.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Design; Humans; Naphthoquinones; Neoplasms; Patents as Topic; Tabebuia

Quinones are among the most studied natural and synthetic products in the literature because they have considerable biological potential. These compounds exhibit activity against many microorganisms and are able to eliminate tumor cells through several mechanisms of action. Some of these compounds have become drugs that are used clinically. However, they also have problems with respect to solubility, stability and toxicity. The alternative of using controlled-release systems has been applied to quinones, with good results in some cases, indicating that these formulations may be a strategy for improving the pharmacological profile of this class of compounds.

Topics: Antineoplastic Agents, Phytogenic; Biological Availability; Biological Products; Cell Survival; Humans; Naphthoquinones; Neoplasms; Solubility

Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. β-Lapachone (β-lap) is a novel anticancer agent whose mechanism of action is highly dependent on. quinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of β-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of β-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of β-lap further decreases the crystallization of β-lap by introducing esterase degradable side chains to the rigid fused ring structure. β-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of β-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints.

Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Drug Design; Humans; Maximum Tolerated Dose; NAD(P)H Dehydrogenase (Quinone); Nanoparticles; Nanotechnology; Naphthoquinones; Neoplasms; Prodrugs

Recently, a wide range of food-derived phytochemical compounds and their synthetic derivatives have been proposed for cancer treatment. Unfortunately, data available in related literature focus on the anti-cancer properties of compounds derived from edible plants, while very little is known about those derived from non-edible plants. And thus, the underlying mechanisms of their anti-cancer effects are yet to be elucidated. This review collates the available data on the anti-cancer activities of six phytochemical-derived compounds from edible and non-edible plants, i.e. rottlerin, berbamine, sparstolonin B, sulforaphane, plumbagin and 6-shogaol. These compounds are used as bioactive markers for cytotoxicity against tumors. As such, understanding their mode of action will provide the rationale for the combination strategies of these compounds with other drugs in the battle against cancer.

Topics: Acetophenones; Antineoplastic Agents, Phytogenic; Benzopyrans; Benzylisoquinolines; Catechols; Heterocyclic Compounds, 4 or More Rings; Humans; Isothiocyanates; Naphthoquinones; Neoplasms; Phytotherapy; Plant Extracts; Signal Transduction; Sulfoxides

Survivin belongs to the family of apoptosis inhibitors (IAPs), which antagonizes the induction of cell death. Dysregulated expression of IAPs is frequently observed in cancers, and the high levels of survivin in tumors compared to normal adult tissues make it an attractive target for pharmacological interventions. The small imidazolium-based compound YM155 has recently been reported to block the expression of survivin via inhibition of the survivin promoter. Recent data, however, question that this is the sole and main effect of this drug, which is already being tested in ongoing clinical studies. Here, we critically review the current data on YM155 and other new experimental agents supposed to antagonize survivin. We summarize how cells from various tumor entities and with differential expression of the tumor suppressor p53 respond to this agent in vitro and as murine xenografts. Additionally, we recapitulate clinical trials conducted with YM155. Our article further considers the potency of YM155 in combination with other anti-cancer agents and epigenetic modulators. We also assess state-of-the-art data on the sometimes very promiscuous molecular mechanisms affected by YM155 in cancer cells.

Topics: Animals; Apoptosis; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Mice; Naphthoquinones; Neoplasms; Promoter Regions, Genetic; Survivin; Xenograft Model Antitumor Assays

Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair. The role of PARP proteins in DNA repair is of particular interest, in view of the finding that certain tumors defective in homologous recombination mechanisms, may rely on PARP-mediated DNA repair for survival, and are sensitive to its inhibition. PARP inhibitors may also increase tumor sensitivity to DNA-damaging agents. Clinical trials of PARP inhibitors are investigating the utility of these approaches in cancer. The hyperactivation of PARP has also been shown to result in a specific programmed cell death pathway involving NAD+/ATP depletion, mu-calpain activation, loss of mitochondrial membrane potential, and the release of apoptosis inducing factor. Hyperactivation of the PARP pathway may be exploited to selectively kill cancer cells. Other PARP forms, including tankyrase 1 (PARP 5a), which plays an important role in enhancing telomere elongation by telomerase, have been found to be potential targets in cancer therapy. The PARP pathway and its inhibition thus offers a number of opportunities for therapeutic intervention in both cancer and other disease states.

Topics: Animals; Disease Models, Animal; DNA Repair; Enzyme Inhibitors; Epigenesis, Genetic; Humans; Molecular Targeted Therapy; Nanomedicine; Naphthoquinones; Necrosis; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Transcription Factors

Topics: Actinobacteria; Biological Products; Heterocyclic Compounds; Naphthoquinones; Neoplasms; Phenazines; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Wnt Signaling Pathway

A large number of natural products including several synthetic drugs possess naphthoquinone chromophore. Various methods have been devised for their synthesis. Several naphthoquinone derivatives have been found to possess diverse biological properties especially anticancer activity which has stimulated keen interest and research in this field.. The present review provides recent therapeutic patent literature (2000 - 2012) describing the applications of naphthoquinones and their derivatives on anticancer activities. Information from articles published in international peer-reviewed journals has been included to comprise a more exhaustive review.. With the advent of stem cell research and molecular mechanism associated with cure of cancer, the use of classical and novel naphthoquinone structures have been more frequently noted in recent (2000 - 2012) patented agents for treatment of cancer.

Topics: Animals; Antineoplastic Agents; Drug Design; Humans; Naphthoquinones; Neoplasms; Patents as Topic

Shikonin is the major constituent of the root of Lithospermum erythrorhizon, which has been used in traditional Chinese medicine to treat external wounds, burns, or dermatitis for centuries. Nowadays, this root is commonly used as an herbal medicine against cancer. Studies carried out over the past 30 years have demonstrated that many of the effects historically associated with the use of this root have a scientific basis, with shikonin and its derivatives being responsible for its pharmacological properties. These include both anti-inflammatory and anticancer effects. While previous summaries have focused on the pharmacokinetics and toxicity of shikonin, the aim of this review is to report on the most current findings with regard to shikonin's antitumor activity by summarizing and comparing the various studies published in the last ten years and discussing the pharmacological aspects that make shikonin a promising anticancer agent.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Humans; Medicine, Chinese Traditional; Naphthoquinones; Neoplasms; Plant Roots

Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activities of these substances for the development of drugs against the neglected diseases leishmaniasis and Chagas disease as well as malaria, tuberculosis and cancer. Three strategies used to develop bioactive naphthoquinoidal compounds are discussed: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Among these strategies, reactions such as copper-catalysed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, and heterocyclisations will be discussed for the development of naphthoquinoidal compounds against Trypanosoma cruzi, Leishmania and cancer. The aim of derivatisation is the generation of novel molecules that inhibit cellular organelles/processes, generate reactive oxygen species (ROS) and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against neglected diseases and cancer.

Topics: Animals; Cell Membrane; Chagas Disease; Humans; Hydrophobic and Hydrophilic Interactions; Leishmania; Leishmaniasis; Malaria; Naphthoquinones; Neoplasms; Reactive Oxygen Species; Trypanosoma cruzi; Tuberculosis

Quinones are plant-derived secondary metabolites that present some anti-proliferation and anti-metastasis effects in various cancer types both in vitro and in vivo. This review focuses on the anti-cancer prospects of plant-derived quinones, namely, aloe-emodin, juglone, β-lapachol, plumbagin, shikonin, and thymoquinone. We intend to summarize their anti-cancer effects and investigate the mechanism of actions to promote the research and development of anti-cancer agents from quinones.

Topics: Anthraquinones; Antineoplastic Agents, Phytogenic; Benzoquinones; Cell Line, Tumor; Cell Survival; Humans; Naphthoquinones; Neoplasms; Plant Extracts

Covering: 1997 to 2010. The angucycline group is the largest group of type II PKS-engineered natural products, rich in biological activities and chemical scaffolds. This stimulated synthetic creativity and biosynthetic inquisitiveness. The synthetic studies used five different strategies, involving Diels-Alder reactions, nucleophilic additions, electrophilic additions, transition-metal mediated cross-couplings and intramolecular cyclizations to generate the angucycline frames. Biosynthetic studies were particularly intriguing when unusual framework rearrangements by post-PKS tailoring oxidoreductases occurred, or when unusual glycosylation reactions were involved in decorating the benz[a]anthracene-derived cores. This review follows our previous reviews, which were published in 1992 and 1997, and covers new angucycline group antibiotics published between 1997 and 2010. However, in contrast to the previous reviews, the main focus of this article is on new synthetic approaches and biosynthetic investigations, most of which were published between 1997 and 2010, but go beyond, e.g. for some biosyntheses all the way back to the 1980s, to provide the necessary context of information.

Topics: Aminoglycosides; Anthraquinones; Anti-Bacterial Agents; Biological Products; Biosynthetic Pathways; Carbohydrate Sequence; Cell Line, Tumor; Coumarins; Glycosides; Glycosylation; Humans; Isoquinolines; Molecular Structure; Naphthoquinones; Neoplasms; Polyketides; Quinones; Streptomyces; Structure-Activity Relationship

Quinones represent a large and diverse class of antitumor drugs and many quinones are approved for clinical use or are currently undergoing evaluation in clinical trials. For many quinones reduction to the hydroquinone has been shown to play a key role in their antitumor activity. The two-electron reduction of quinones by NQO1 has been shown to be an efficient pathway to hydroquinone formation. NQO1 is expressed at high levels in many human solid tumors making this enzyme ideally suited for intracellular drug activation. Cellular levels of NQO1 are influenced by the NQO1*2 polymorphism. Individuals homozygous for the NQO1*2 allele are NQO1 null and homozygous NQO1*2*2 cell lines have been shown to be more resistant to antitumor quinones when compared to isogenic cell lines overexpressing NQO1. In this review we will discuss the role of NQO1 in the sensitivity and resistance of human cancers to the quinone antitumor drugs mitomycin C, β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors including 17-AAG. The role of NQO1 in the bioreductive activation of mitomycin C remains controversial but pre-clinical data strongly suggests a role for NQO1 in the activation of β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors. Despite a large volume of preclinical data demonstrating that NQO1 is an important determinant of sensitivity to these antitumor quinones there is little information on whether the clinical response to these agents is influenced by the NQO1*2 polymorphism. The availability of simple assays for the determination of the NQO1*2 polymorphism should facilitate clinical testing of this hypothesis.

Topics: Antineoplastic Agents; Benzoquinones; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mitomycin; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Polymorphism, Genetic; Quinones; Rifabutin

Shikonin, the main active ingredient of Lithospermum, and its derivatives have been proved to have antitumor effects, and the anti-tumor mechanisms involve multiple targets. Based on recent literatures, this review focuses on the antitumor effects and its mechanisms. More emphases are given on the aspects of induction of apoptosis, induction of necrosis, acting on matrix metalloproteinase, acting on the protein tyrosine kinase and antiangiogenesis. The current status and problems of shikonin derivatives in antitumor effects are simply summarized and lookout for the development of antitumor drugs with shikonin as leading compounds.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Drugs, Chinese Herbal; Humans; Lithospermum; Matrix Metalloproteinase 9; Naphthoquinones; Necrosis; Neoplasms; Neovascularization, Pathologic; Plants, Medicinal; Protein-Tyrosine Kinases; Reactive Oxygen Species

Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects.. Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed.. At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.

Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Design; Humans; Lithospermum; Naphthoquinones; Neoplasms; Patents as Topic; Plant Extracts

Survivin is a member of the inhibitors-of-apoptosis protein (IAPs) family. It promotes cell survival through interference with multiple cell cycle-related proteins such as INCENP and Aurora B kinase. Survivin also inhibits cell death through interference with both caspase-dependent and -independent cell apoptosis. Interestingly, recent evidence suggests that survivin may also play a role in the regulation of cancer cell autophagy. At the clinical level, studies on clinical specimens have shown that survivin expression is up-regulated in various human cancers and its up-regulation is associated with tumour resistance to both chemotherapy and radiation therapy. On the basis of these findings, survivin has been proposed as an attractive target for new anti-cancer interventions. However, despite the role that survivin plays in cancer cell survival and anti-drug response, the development of survivin inhibitors is relatively slow as compared to other therapeutic inhibitors for cancer treatment. In this review, the relationships between survivin expression and the causation of drug resistance in cancers are re-addressed. This review also summarizes the recent development of survivin inhibitors for clinical usage.

Topics: Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Naphthoquinones; Neoplasms; RNA, Small Interfering; Survivin

The proteasome is a multicatalytic protease complex whose activity is required for the growth of normal or tumor cells. It has been shown that human cancer cells are more sensitive to proteasome inhibition than normal cells, indicating that the proteasome could be a target of chemotherapy. Studies suggest that traditional Chinese medicine (TCM) is an effective approach for cancer treatment. Here we reviewed several TCMs for their potential in treatment of cancer. This short review focuses mainly on the TCMs that potentially target the tumor cellular proteasome and NF-kappaB pathway whose activation is dependent on the proteasome activity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Benzyl Compounds; Curcumin; Diterpenes; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Epoxy Compounds; Humans; Medicine, Chinese Traditional; Molecular Structure; Naphthoquinones; Neoplasms; Pentacyclic Triterpenes; Phenanthrenes; Phenols; Proteasome Endopeptidase Complex; Signal Transduction; Triterpenes

Malignant tumor, one of the most refractory diseases, plays a threaten role in human health, the therapy and research on malignant tumor have taken a long way to go. The anti-tumor drugs which are the essential therapy strategies upgrade with the development of new anti-tumor targets and the research on tumor pathogenesis. Aurora kinase and Pin1, the novel anti-tumor targets, maintain the important relationship with tumor. Many new compounds designed on these targets have excellent anti-tumor effects and also enter into phase I or phase II clinical trial.

Topics: Antineoplastic Agents; Apoptosis; Aurora Kinases; Humans; Naphthoquinones; Neoplasms; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Piperazines; Protein Serine-Threonine Kinases

Discovered 10 years ago, survivin has a dual role in the smooth progress of mitosis and in apoptosis resistance. Survivin plays an important physiological role in development, but is absent in differentiated adult tissues. In contrast, aberrant survivin expression is found in most human cancers because of the activation of various signalling pathways. A complex survivin network appears to intersect multiple pathways in cell biology, related to several molecular partners and fine subcellular localizations. Based on its pro-oncogenic properties, basic and translational studies have shown a growing interest in survivin that has led to consider survivin as a prognostic marker and a promising target for anti-tumoral therapies.

Topics: Animals; Animals, Genetically Modified; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Cancer Vaccines; Cell Cycle; Clinical Trials, Phase I as Topic; Drug Delivery Systems; Drug Screening Assays, Antitumor; Embryonic Development; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Models, Biological; Naphthoquinones; Neoplasm Proteins; Neoplasms; Recombinant Fusion Proteins; Subcellular Fractions; Survivin; tat Gene Products, Human Immunodeficiency Virus

The CDC25 phosphatases are key regulators of normal cell division and the cell's response to DNA damage. Earlier studies suggested non-overlapping roles for each isoform during a specific cell cycle phase. However, recent data suggest that multiple CDC25 isoforms cooperate to regulate each cell cycle transition. For instance, although CDC25A was initially thought to exclusively regulate the G(1)-S transition, recent data demonstrate a significant role for CDC25A in the G(2)-M transition. Further evidence demonstrates that in addition to the ATM/ATR-CHK pathway, a p38-MAPKAP pathway is also involved in controlling CDC25 activity during G(2)/M checkpoint activation. Together with the fact that CDC25 overexpression is reported in many cancers, these data highlight the significance of developing specific CDC25 inhibitors for cancer therapy.

Topics: Animals; Benzoquinones; cdc25 Phosphatases; Cell Cycle; Cell Cycle Proteins; Humans; Isoenzymes; Models, Biological; Naphthoquinones; Neoplasms; Quinolones; Quinones; Thiazoles

Defective or abortive repair of DNA lesions has been associated with carcinogenesis. Therefore it is imperative for a cell to accurately repair its DNA after damage if it is to return to a normal cellular phenotype. In certain circumstances, if DNA damage cannot be repaired completely and with high fidelity, it is more advantageous for an organism to have some of its more severely damaged cells die rather than survive as neoplastic transformants. A number of DNA repair inhibitors have the potential to act as anticarcinogenic compounds. These drugs are capable of modulating DNA repair, thus promoting cell death rather than repair of potentially carcinogenic DNA damage mediated by error-prone DNA repair processes. In theory, exposure to a DNA repair inhibitor during, or immediately after, carcinogenic exposure should decrease or prevent tumorigenesis. However, the ability of DNA repair inhibitors to prevent cancer development is difficult to interpret depending upon the system used and the type of genotoxic stress. Inhibitors may act on multiple aspects of DNA repair as well as the cellular signaling pathways activated in response to the initial damage. In this review, we summarize basic DNA repair mechanisms and explore the effects of a number of DNA repair inhibitors that not only potentiate DNA-damaging agents but also decrease carcinogenicity. In particular, we focus on a novel anti-tumor agent, beta-lapachone, and its potential to block transformation by modulating poly(ADP-ribose) polymerase-1.

Topics: Anticarcinogenic Agents; Cell Transformation, Neoplastic; DNA Breaks, Double-Stranded; DNA Breaks, Single-Stranded; DNA Repair; Humans; Models, Biological; Naphthoquinones; Neoplasms; Poly(ADP-ribose) Polymerases

Therapeutic biology is an exciting new frontier in the post-genomic era with the mission to better human health. The explosive increase in the understanding of molecular and regulatory biology has enabled the identification of a plethora of potential targets and pathways for the discovery of new medicines. Conversely, molecularly based therapeutic intervention of biological aberrations in human diseases offers a test of the depth of our understanding of biology. This article discusses three examples of therapeutic biology research. The first concerns the treatment of cancer by activating genome surveillance circuitry, namely checkpoint-pathway activation therapy. The second example is the identification of the HIV Tat protein as both a cause of immune cell activation and apoptosis, and as a vaccine candidate against HIV infection. The third example describes transkingdom RNA interference and its application in the investigational and therapeutic silencing of disease genes.

Topics: AIDS Vaccines; Animals; Gene Products, tat; Genes, cdc; Genomics; Humans; Lymphocyte Activation; Naphthoquinones; Neoplasms; Radiation-Sensitizing Agents; RNA Interference; Signal Transduction; T-Lymphocytes; Therapeutics

Work from the laboratory of Dr. Arthur B. Pardee has highlighted basic principles that govern cellular and molecular biological processes in living cells. Among the most important governing principles in cellular and molecular responses are: (i) threshold "restriction" responses, wherein a level of response is reached and a "point of no return" is achieved; (ii) feedback regulation; and (iii) redundancy. Lessons learned from the molecular biology of cellular stress responses in mammalian cancer versus normal cells after ionizing radiation (IR) or chemotherapeutic agent exposures reveal similar instances of these guiding principles in mammalian cells. Among these are the: (i) induction of cell death responses by beta-lapachone (beta-lap), a naphthoquinone anti-tumor agent that kills cancer cells via an NQO1 (i.e., X-ray-inducible protein-3, xip3)-dependent mechanism; (ii) induction of secretory clusterin (sCLU) in response to TGF-beta1 exposure, and the ability of induced sCLU protein to down-regulate TGF-beta1 signaling; and (iii) induction of DNA mismatch repair-dependent G(2) cell cycle checkpoint responses after exposure to alkylating agents. We have learned these lessons and now adopted strategies to exploit them for improved therapy. These examples will be discussed and compared to the pioneering findings of researchers in the Pardee laboratory over the years.

Topics: Apoptosis; Cell Cycle; Cell Death; Cell Physiological Phenomena; Clusterin; DNA Mismatch Repair; Feedback, Physiological; Humans; Naphthoquinones; Neoplasms; Radiation-Sensitizing Agents

Cancer will be the major cause of death in the 21st century and natural products should provide novel and more effective anticancer agents. This review deals with new natural molecules liable to become anticancer drugs, as well as recent specific strategies for a selective treatment of cancer. The introduction presents the current state of the art on anticancer research. Beside, in the following subheadings we summarize our research on cytotoxic natural quinone methide-triperpenes and their analogues. We also discuss our results on the anti-tumour promoting activity of natural naphthoquinones and their derivatives.

Topics: Animals; Antineoplastic Agents; Biological Products; Humans; Naphthoquinones; Neoplasms; Structure-Activity Relationship; Triterpenes

Topics: Animals; Antineoplastic Agents; Cytosol; Electron Spin Resonance Spectroscopy; Humans; Liver Extracts; Microsomes; Molecular Structure; NADP; NADPH-Ferrihemoprotein Reductase; Naphthoquinones; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species

Topics: Animals; Cosmetics; Female; Germany; Government Agencies; Hair Color; Hair Dyes; Humans; Male; Naphthoquinones; Neoplasms; Radiation Injuries; Risk Assessment; Risk Factors; Sunscreening Agents; Tattooing; Vitamin A; Zinc Oxide

The naphthoquinone pigment, shikonin, isolated from Lithospermum erythrorhizon Sieb. et Zucc.(Boraginaceae) and its derivatives are the active components isolated from the Chinese herbal therapeutic, Zicao. Historically, Zicao root extracts have been used to treat macular eruption, measles, sore-throat, carbuncles and burns. Multiple pharmacological actions have been attributed to shikonin, e.g. antiinflammatory, antigonadotropic and anti-HIV-1 activity. In this review, several therapeutic applications of shikonin will be summarized including its pleiotropic, antiinflammatory and antitumour effects. Widely diverse and sometimes conflicting activities have been attributed to shikonin, e.g. wound healing, enhanced granuloma formation, suppression of local acute inflammatory reactions, inhibition of angiogenesis, inhibition of select chemokine ligands, inhibition of DNA topoisomerase activity, inhibition of platelet activation and antimicrobial activity. Comparison of the various reported mechanisms of action for shikonin lead us to hypothesize that shikonin is an effective inhibitor of protein-protein interaction with multiple targets in both the intracellular and extracellular compartments. This general inhibitory effect can account for the broad spectrum of shikonin biological and pharmacological activities.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Granuloma; Humans; Inflammation; Lithospermum; Mast Cells; Naphthoquinones; Neoplasms; Neutrophils; Phytotherapy; Plant Extracts; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Respiratory Burst; Signal Transduction; Wound Healing

Beta-lapachone is an ortho naphthoquinone, originally isolated from a tree whose extract has been used medicinally for centuries. Recent investigations suggest its potential application against numerous diseases. Its lethality at micromolar ( m) concentrations against a variety of cancer cells in culture indicates its potential against tumor growth. A few experiments with positive results have been performed that apply the compound to tumors growing in animals. Particularly promising is the remarkably powerful synergistic lethality between beta-lapachone and taxol against several tumor cell lines implanted into mice; the mice did not appear to be adversely affected. Enhanced lethality of X-rays and alkylating agents to tumor cells in culture was reported when beta-lapachone was applied during the recovery period, because of inhibition of DNA lesion repair. Clinical trials are still to be initiated. The detailed mechanism of cell death induced by beta-lapachone remains for investigation. DNA topoisomerase I was the first biochemical target of beta-lapachone to be discovered, although its role in cell death is not clear. A proposed mechanism of cell death is via activation of a futile cycling of the drug by the cytoplasmic two-electron reductase NAD(P) H: quinone oxidoreductase, also known as NQO1, DT-diaphorase and Xip3. Death of NQO1 expressing cells is prevented by the NQO1 inhibitor dicoumarol, and cells with low NQO1 are resistant. At higher drug concentrations the production of reactive oxygen species (ROS) appears to be responsible. Furthermore, this process is p53- and caspase- independent. Either apoptotic or necrotic cell death can result, as reported in various studies performed under differing conditions. Beta-lapachone is one of a few novel anticancer drugs currently under active investigation, and it shows promise for chemotherapy alone and especially in combinations.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Brazil; Drug Therapy, Combination; Humans; Naphthoquinones; Neoplasms; Plants, Medicinal

beta-lapachone (beta-lap) is a lipophilic o-naphthoquinone isolated from the bark of the lapacho tree. Initial observations proved its capability for inhibiting growth of Yoshida tumor and Walker 256 carcinosarcoma. beta-Lap redox-cycling in the presence of reductants and oxygen yields "reactive oxygen species" (ROS: O2-, OH and H2O2) which cytotoxicity led to assume its role in beta-lap activity in cells. beta-Lap inhibited DNA synthesis in Trypanosoma cruzi as well as topoisomerases I and II, poly(ADP-ribose) polymerase (PARP) in different cells. These enzymes are essential for maintaining DNA structure. beta-Lap inhibited growth of a large variety of tumor cells including epidermoid laringeal cancer, prostate, colon, ovary and breast cancer and also different types of leukemia cells. Advances in knowledge of apoptosis ("programmed cell death") and necrosis provided useful information for understanding the mechanism of beta-lap cytotoxicity. Thiol-dependent proteases (Calpaine), kinases (e.g. c-JUN NH2-terminal kinase), caspases and nucleases are involved in beta-lap cytotoxicity. These enzymes activity, as well as ROS production by beta-lap redox-cycling, would be essential for beta-lap cytotoxicity. Diaphorase and NAD(P)H-quinone reductase, which catalyse beta-lap redox-cycling and ROS production, seem to play an essential role in beta-lap activity. On these grounds, clinical applications of beta-lap have been suggested.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma 256, Walker; Humans; Naphthoquinones; Neoplasms; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Sarcoma, Yoshida; Topoisomerase I Inhibitors

Pneumocystis carinii pneumonitis (PCP) is one of the most important opportunistic infections in children and adolescents with cancer. Its high frequency and a considerable mortality have led to primary chemoprophylaxis in patients with hematological malignancies and following allogeneic hematopoietic stem cell transplantation. Although less well characterized, patients with autologous stem cell transplantation and patients with dose-intensive chemotherapy for pediatric solid tumors may have a similarly high risk for PCP based on their profound T-cell depletion. For more than two decades, effective chemoprophylaxis for PCP has been available. Trimethoprim and sulfamethoxazole (TMP/SMX) is the prophylactic modality of first choice. The combination has been shown to be almost 100 % efficacious in pediatric cancer patients at highest risk, and it is usually well tolerated in this setting. Secondary alternatives to TMP/SMX include oral dapsone, oral atovaquone, and aerosolized pentamidine-isethionate. These modalities are less effective than TMP/SMX, and have been evaluated predominantly in HIV-infected patients. This article reviews epidemiology and current approaches to chemoprophylaxis for PCP in children and adolescents with cancer and/or hematopoietic stem cell transplantation, and provides evidence-based guidelines for indications and modalities of PCP prophylaxis in this population.

Topics: Adolescent; Age Factors; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Atovaquone; Child; Child, Preschool; Dapsone; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Naphthoquinones; Neoplasms; Odds Ratio; Pentamidine; Pneumonia, Pneumocystis; Practice Guidelines as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination

The cyclotron-produced radiohalogen, 211At, is eminently suitable as a possible therapeutic radionuclide. It decays by the emission of 6.8 MeV mean energy alpha-particles, which from a radiobiological viewpoint are of near optimal therapeutic LET. This paper reviews developments in the possible application of [211At]astato-labelled molecules as potential anti-tumour agents. Additionally, radio-dosimetric evidence is presented, and its implications for human cancer therapy are discussed.

Topics: Animals; Antibodies, Monoclonal; Astatine; Humans; Melanoma; Naphthoquinones; Neoplasms; Nucleic Acid Precursors; Radiotherapy Dosage

Several radiopharmaceuticals have recently been shown to have a considerable affinity for malignant tissue. All the tumor-seeking radiopharmaceuticals in current use are nonspecific and may also be picked up by benign tumors and infectious processes, including abscess and granuloma. The sensitivity of the tumor-imaging procedure depends on the radiopharmaceutical employed, the type of tumor, its size and location, and previous or current treatment. Gallium-67 citrate (67Ga), the most widely used tumor-seeking radiopharmaceutical, seems to have its greatest value in detecting bronchogenic carcinomas irrespective of cell type. The sensitivity for lung cancer in 489 studies was 93 per cent. Gallium-67 is also of great value in the staging of Hodgkin's disease, in which its sensitivity is 87 per cent. Non-Hdgkin's lymphomas are detected with only slightly lower sensitivity. There is, in fact, evidence that 67Ga is at least complemenatry, if not more sensitive than lymphangiography, in the staging of lymphoma. However, adenocarcinomas originating in the gastrointestinal tract are detected by 67Ga with a sensitivity of only about 40 per cent, whereas various chelates of bleomycin (including 111In-Bleo, 99mTc-Bleo and 57Co-Bleo) detect adenocarcinoma of the gastrointestinal tract with considerably higher sensitivity. In the few studies available comparing bleomycin chelates, 57Co-Bleo and 99mTc-Bleo appear to be more sensitive in detecting tumor than 111In-Bleo. Other tumor-seeking radiopharmaceuticasl which have been employed with somewhat less success include selenium compounds, labeled pyrimidines, several inorganic cations, lanthanide chelates and labeled proteins. Yet to be evaulated clinically is the efficacy of radiolabeled antibodies which are specific for tumor antigens, such as 131I-anti-CEA (carcinoembryonic antigen).

Topics: Antibodies, Neoplasm; Bismuth; Bleomycin; Carcinoembryonic Antigen; Cesium Radioisotopes; Chelating Agents; Chloroquine; Cobalt Radioisotopes; Copper; Gallium Radioisotopes; Glycerophosphates; Humans; Indium; Mercury Radioisotopes; Metals, Rare Earth; Naphthoquinones; Neoplasms; Porphyrins; Proteins; Pyrimidines; Radioisotopes; Radionuclide Imaging; Selenium; Technetium; Tetracycline

Some pharmacologic properties of nine antitumor agents from higher plants are described. The agents are vincristine, vinblastine the epiodophyllotoxin derivatives VM-26 and VP-16-213, maytansine, bruceantin, thalicarpine, camptothecin, and lapachol. When sufficient information is available, the agents are discussed with regard to their antitumor activity, mechanism of action, pharmacologic disposition, structure-activity relationships, and toxicity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aporphines; Camptothecin; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Etoposide; Humans; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Maytansine; Melanoma; Naphthoquinones; Nasopharyngeal Neoplasms; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Structure-Activity Relationship; Teniposide; Vinblastine; Vincristine

Topics: Antifibrinolytic Agents; Bromodeoxyuridine; Dactinomycin; DNA; DNA, Neoplasm; Ethylmaleimide; Hyperbaric Oxygenation; Naphthoquinones; Neoplasms; Retinoids; Vitamin K

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death.. We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200).. ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Cell Line, Tumor; DNA Damage; Female; Humans; Male; Middle Aged; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Necrosis; Neoplasms; Reactive Oxygen Species

The analysis was designed to compare the pharmacokinetics (PK) of sepantronium between US and Japanese patient populations using data obtained from two phase 1 studies being conducted in a similar design, one conducted in the USA and the other in Japan. Patients with a confirmed advanced solid tumor or non-Hodgkin lymphoma (NHL) (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these studies. Sepantronium bromide was administered as a continuous intravenous infusion for 168 h (7 days) every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 h after termination of sepantronium bromide infusion. Forty-one subjects in the US study (including five patients with NHL) and 33 patients in the Japanese study were enrolled in both studies and 35 in US and 32 in Japan had adequate samples for PK evaluation. The PK parameters were calculated by non-compartment analysis method and were compared in the US and Japanese populations. The geometric mean ratios (90% confidence intervals) of area under the concentration-time curve, steady state concentration and amount excreted into urine between Japanese and US populations were 1.068 (0.932-1.224), 1.141 (0.996-1.307) and 0.981 (0.855-1.125), respectively. There appear to be no PK differences between the US and Japanese patients with solid tumors or NHL.

Topics: Antineoplastic Agents; Area Under Curve; Asian People; Humans; Imidazoles; Infusions, Intravenous; Naphthoquinones; Neoplasms; United States; White People

YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors.. Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles.. Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients.. YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Fever; Humans; Imidazoles; Infusions, Intravenous; Inhibitor of Apoptosis Proteins; Male; Metabolic Clearance Rate; Microtubule-Associated Proteins; Middle Aged; Naphthoquinones; Neoplasms; Patient Dropouts; Survivin; Treatment Outcome

To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin.. Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion.. Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response. CONCLUSION YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Imidazoles; Infusions, Intravenous; Inhibitor of Apoptosis Proteins; Male; Maximum Tolerated Dose; Microtubule-Associated Proteins; Middle Aged; Naphthoquinones; Neoplasm Proteins; Neoplasms; Pilot Projects; Survivin; Treatment Outcome

Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfa- methoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day -5 until day -1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC >0.5 x 109/l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P < 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels (n = 1), nausea or vomiting (n = 3), thrombocytopenia (n = 2) and neutropenia (n = 2). All episodes of TMP/SMP intolerance occurred following transplantation after a median duration of 17.5 (range 2-48) days and a median of 7 (range 1-20) doses. Resolution of adverse side-effects occurred in all eight patients within a median of 7 (range 2-20) days following discontinuation of therapy. Neither PCP nor bacterial infections were identified in any of the patients treated. This prospective randomized study demon

Topics: Adult; Aged; Antifungal Agents; Atovaquone; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Male; Middle Aged; Naphthoquinones; Neoplasms; Pneumocystis; Pneumonia, Pneumocystis; Prospective Studies; Transplantation, Autologous; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation; Humans; Leukemia, Myeloid; Naphthoquinones; Neoplasms; Plant Extracts; Time Factors

Nowadays, Fenton chemistry-based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H

Topics: Apoptosis; Ferric Compounds; Ferroptosis; Glutathione; Metals; Naphthoquinones; Neoplasms; Phenols

The stemness characteristics of cancer cells, such as self-renewal and tumorigenicity, are considered to be responsible, in part, for tumor metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in promoting both stemness and tumor metastasis. Although the traditional medicine juglone is thought to play an anticancer role by affecting cell cycle arrest, induction of apoptosis, and immune regulation, a potential function of juglone in regulating cancer cell stemness characteristics remains unknown.. In the present study, tumor sphere formation assay and limiting dilution cell transplantation assays were performed to assess the function of juglone in regulating maintenance of cancer cell stemness characteristics. EMT of cancer cells was assessed by western blot and transwell assay. Data gathered indicates juglone inhibits stemness characteristics and EMT in cancer cells. Furthermore, we verified that metastasis was suppressed by juglone treatment. We also observed that these effects were, in part, achieved by inhibiting Peptidyl-prolyl. These results indicate that juglone inhibits maintenance of stemness characteristics and metastasis in cancer cells.

Topics: Apoptosis; Blotting, Western; Epithelial-Mesenchymal Transition; Naphthoquinones; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells

The ability to control the activation of prodrugs by transition metals has been shown to have great potential for controlled drug release in cancer cells. However, the strategies developed so far promote the cleavage of C-O or C-N bonds, which limits the scope of drugs to only those that present amino or hydroxyl groups. Here, we report the decaging of an

Topics: Animals; Humans; Naphthoquinones; Neoplasms; Palladium; Prodrugs; Zebrafish

A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors such as half-wave potentials, hydrophobicity and molar refractivity. Compounds

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Molecular Docking Simulation; Naphthoquinones; Neoplasms; TOR Serine-Threonine Kinases

Microwave (MW) thermal therapy has been widely used for the treatment of cancer in clinics, but it still shows limited efficacy and a high recurrence rate owing to non-selective heat delivery and thermo-resistance. Regulating glycolysis shows great promise to improve MW thermal therapy since glycolysis plays an important role in thermo-resistance, progression, metabolism, and recurrence. Herein, we developed a delivery nanosystem of shikonin (SK)-loaded and hyaluronic acid (HA)-modified hollow Fe-MOF (HFM), HFM@SK@HA, as an efficient glycolysis-meditated agent to improve the efficacy of MW thermal therapy. The HFM@SK@HA nanosystem shows a high SK loading capacity of 31.7 wt %. The loaded SK can be effectively released from the HFM@SK@HA under the stimulation of an acidic tumor microenvironment and MW irradiation, overcoming the intrinsically low solubility and severe toxicity of SK. We also find that the HFM@SK@HA can not only greatly improve the heating effect of MW in the tumor site but also mediate MW-enhancing dynamic therapy efficiency by catalyzing the endogenous H

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Hep G2 Cells; Humans; Iron; L Cells; Metal Nanoparticles; Metal-Organic Frameworks; Mice; Microwaves; Naphthoquinones; Neoplasms; Warburg Effect, Oncologic

The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with β-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chitosan; Doxorubicin; Drug Carriers; Drug Liberation; Female; Humans; Mice, Inbred BALB C; Mitochondria; Nanoparticles; Naphthoquinones; Neoplasms; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Prodrugs; Reactive Oxygen Species; Silicon Dioxide; Tumor Burden

Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (C-C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of β-lapachone (β-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of C-N/C-O bond cleavage-based prodrugs. The designed β-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing β-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1-rich cancer cells over normal cells both in vitro and in vivo. This significantly amplified the therapeutic window of β-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.

Topics: Antineoplastic Agents; Biological Products; Carbon; Cell Line, Tumor; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Prodrugs; Reactive Oxygen Species

cGAS-STING pathway is a key DNA-sensing machinery and emerges as a promising target to overcome the immunoresistance of solid tumors. Here we describe a bovine serum albumin (BSA)/ferritin-based nanoagonist incorporating manganese (II) ions and β-lapachone, which cooperatively activates cGAS-STING signaling in dendritic cells (DCs) to elicit robust adaptive antitumor immunity. Mn

Topics: DNA; Ferritins; Humans; Immunity, Innate; Manganese; Mannose; Membrane Proteins; Naphthoquinones; Neoplasms; Nucleotidyltransferases; Serum Albumin, Bovine; Tumor Microenvironment

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Deubiquitinating Enzymes; DNA Damage; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Membrane Transport Proteins; Naphthoquinones; Neoplasms; Solute Carrier Proteins; Ubiquitin Thiolesterase; Ubiquitin-Specific Proteases

Topics: A549 Cells; Antineoplastic Agents; Coordination Complexes; Humans; MCF-7 Cells; Naphthoquinones; Neoplasms; Phosphines; Ruthenium

Activation of autophagy plays a critical role in DNA repair, especially for the process of homologous recombination. Despite upregulation of autophagy promotes both the survival and the death of cells, the pathways that govern the pro-cell death effects of autophagy are still incompletely understood. YM155 is originally developed as an expression suppressant of BIRC5 (an anti-apoptotic molecule) and it has reached Phase I/II clinical trials for the treatment of variety types of cancer. However, the target-specificity of YM155 has recently been challenged as several studies reported that YM155 exhibits direct DNA damaging effects. Recently, we discovered that BIRC5 is an autophagy negative-modulator. Using function-comparative analysis, we found in the current study that YM155 and BIRC5 siRNA both induced early "autophagy-dependent ROS production-mediated" DNA damage/strand breaks and concurrently downregulated the expression of RAD54L, RAD51, and MRE11, which are molecules known for their important roles in homologous recombination, in human cancer (MCF7, MDA-MB-231, and SK-BR-3) and mouse embryonic fibroblast (MEF) cells. Similar to the effects of YM155 and BIRC5 siRNA, downregulation of RAD54L and RAD51 by siRNA induced autophagy and DNA damage/strand breaks in cells, suggesting YM155/BIRC5 siRNA might also induce autophagy partly through RAD54L and RAD51 downregulations. We further observed that prolonged YM155 and BIRC5 siRNA treatment induced autophagic vesicle formation proximal to the nucleus and triggered DNA leakage. In conclusion, our findings reveal a novel mechanism of action of YM155 (i.e. induces autophagy-dependent ROS production-mediated DNA damage) in cancer cells and show the functional complexity of BIRC5 and autophagy involving the modulation of genome stability, highlighting that upregulation of autophagy is not always beneficial to the DNA repair process. Our findings can aid the development of a variety of BIRC5-directly/indirectly targeted anticancer therapies that are currently under pre-clinical and clinical investigations.

Topics: Antineoplastic Agents; Autophagy; Cell Line, Tumor; DNA Repair; Down-Regulation; Genomic Instability; Humans; Imidazoles; Naphthoquinones; Neoplasms; Reactive Oxygen Species; Survivin

β-Lapachone is a classic quinone-containing antitumor NQO1-bioactivatable drug that directly kills NQO1-overexpressing cancer cells. However, the clinical applications of β-lapachone are primarily limited by its high toxicity and modest lethality. To overcome this side effect and expand the therapeutic utility of β-lapachone, we demonstrate the effects of a novel combination therapy including β-lapachone and the proliferating cell nuclear antigen (PCNA) inhibitor T2 amino alcohol (T2AA) on various NQO1

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; DNA Damage; DNA Repair; Female; G1 Phase; Humans; MCF-7 Cells; Mice; Mice, Inbred C57BL; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Oxidative Stress; Proliferating Cell Nuclear Antigen; Reactive Oxygen Species

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; DNA Topoisomerases, Type II; Drug Design; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; MCF-7 Cells; Molecular Docking Simulation; Naphthoquinones; Neoplasms; Structure-Activity Relationship; Thiadiazines; Topoisomerase II Inhibitors

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Drug Design; Female; Humans; Mice, Inbred BALB C; Molecular Docking Simulation; Molecular Structure; Naphthoquinones; Neoplasms; Protein Binding; S Phase Cell Cycle Checkpoints; STAT3 Transcription Factor; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Nanosized drug delivery systems (NDDSs) have shown excellent prospects in tumor therapy. However, insufficient penetration of NDDSs has significantly impeded their development due to physiological instability and low passive penetration efficiency.. Herein, we prepared a core cross-linked pullulan-modified nanosized system, fabricated by visible-light-induced diselenide bond cross-linked method for transporting β-Lapachone and doxorubicin prodrug (boronate-DOX, BDOX), to improve the physiological stability of the NDDSs for efficient passive accumulation in tumor blood vessels (β-Lapachone/BDOX-CCS). Additionally, ultrasound (US) was utilized to transfer β-Lapachone/BDOX-CCS around the tumor vessel in a relay style to penetrate the tumor interstitium. Subsequently, β-Lapachone enhanced ROS levels by overexpressing NQO1, resulting in the transformation of BDOX into DOX. DOX, together with abundant levels of ROS, achieved synergistic tumor therapy.. In vivo experiments demonstrated that ultrasound (US) + cross-linked nanosized drug delivery systems (β-Lapachone/BDOX-CCS) group showed ten times higher DOX accumulation in the tumor interstitium than the non-cross-linked (β-Lapachone/BDOX-NCS) group.. Thus, this strategy could be a promising method to achieve deep penetration of NDDSs into the tumor.

Topics: Animals; Boronic Acids; Capillary Permeability; Cell Death; Cross-Linking Reagents; Doxorubicin; Drug Delivery Systems; Endocytosis; Female; Glucans; Hep G2 Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Naphthoquinones; Neoplasms; Particle Size; Prodrugs; Reactive Oxygen Species; Tissue Distribution; Ultrasonography

Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer.

Topics: Apoptosis; Cell Death; HeLa Cells; Humans; Melatonin; Naphthoquinones; Neoplasms; Oxidative Stress; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Sirtuin 3; Superoxide Dismutase

Chemotherapy-induced peripheral neuropathy (CIPN) may frequently occur in patients receiving oxaliplatin-based treatment. The aim of the present parallel-group, randomized, controlled pilot trial was to investigate the effect of henna on CIPN in women receiving oxaliplatin-based treatment.. Sixty female patients receiving oxaliplatin-based treatment were randomly divided into two groups, i.e., one intervention group (n = 30) where henna was applied topically and one control group (n = 30) that received routine treatment and care. Women in the intervention group were provided a pack of henna prepared by the investigators following each treatment course (2nd, 3rd, and 4th courses) and were instructed to apply the henna on their palms, fingers, and soles. The chemotherapy-induced peripheral neuropathy assessment tool (CIPNAT) was completed by women subsequent to the 2nd (baseline), 3rd, and 4th courses of treatment.. The present study results showed that henna application on hands and feet has a beneficial effect on peripheral neuropathy. Applying henna is a promising approach in CIPN management.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Middle Aged; Naphthoquinones; Neoplasms; Neuroprotective Agents; Oxaliplatin; Peripheral Nervous System Diseases; Pilot Projects; Random Allocation; Turkey

Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.

Topics: Antineoplastic Agents; Autophagy; Benzofurans; Cell Cycle Proteins; Dasatinib; Drug Repositioning; Epigenomics; Humans; Nanotechnology; Naphthoquinones; Neoplasms; Neoplastic Stem Cells; Protein Kinase Inhibitors; Resveratrol; Signal Transduction; Terpenes

Topics: Antineoplastic Agents; Apoptosis; Cell Line; Fibroblasts; Humans; Naphthoquinones; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Structure-Activity Relationship; Sulfides; Tumor Suppressor Protein p53; Up-Regulation

Topics: A549 Cells; Acrylates; Animals; Antineoplastic Agents; Apoptosis; Benzoates; Drug Design; ErbB Receptors; Humans; Mice, Nude; Molecular Docking Simulation; Naphthoquinones; Neoplasms; Tubulin; Tubulin Modulators

The transcription factor STAT3 is an attractive target for a variety of cancers therapy. Napabucasin, applied in phase III clinical trials for the treatment of a variety of cancers, was regarded as one of the most promising anticancer drug by targeting STAT3. Herein, a novel series of napabucasin derivatives were designed and synthesized, which presented a potent inhibitory activity on a variety of cancers cells. Among the derivatives compound 8q exhibited potent inhibitory activity on U251, HepG2, HT29 and CT26 cells with the IC

Topics: Administration, Oral; Animals; Antineoplastic Agents; Benzofurans; Cell Line; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Mice; Naphthoquinones; Neoplasms; Protein Binding; Solubility; STAT3 Transcription Factor; Structure-Activity Relationship

Hit, Lead & Candidate Discovery Antiangiogenesis therapy is a promising way for treatment of solid cancers, and many angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) or its receptors have been developed. We explored novel antiangiogenic compounds other than anti-VEGF drugs by screening our synthetic compound library and found that 6-thiophen-3-yl-2-methoxy-1,4-naphthoquinone (6-TMNQ) had potential as a novel angiogenesis inhibitor. This paper describes the effects of 6-TMNQ on angiogenesis and tumor growth in vitro and in vivo. 6-TMNQ inhibited serum-, VEGF-, and basic fibroblast growth factor (bFGF)-stimulated proliferation of endothelial cells in a concentration-dependent manner, but had no effect on the proliferation of fibroblasts. VEGF-induced activation of VEGF receptor-2 in endothelial cells was not affected by the compound. 6-TMNQ markedly abrogated both migration and tube formation of endothelial cells. Orally administered 6-TMNQ inhibited angiogenesis in response to VEGF or bFGF in mice in a dose-dependent manner. Furthermore, when tumor-bearing mice were treated with 6-TMNQ, increase in tumor size was significantly prevented due to inhibition of angiogenesis in the tumor tissues. These results demonstrate that 6-TMNQ is an orally available compound that selectively inhibits endothelial cell proliferation and migration, and abrogates angiogenesis, resulting in the prevention of tumor growth. The mechanism of 6-TMNQ action is different from that of conventional anti-VEGF drugs.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Line; Cell Movement; Cell Proliferation; Cell Survival; Endothelial Cells; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Naphthoquinones; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor Receptor-2

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Glutaredoxins; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Nude; Naphthoquinones; Neoplasms; Peroxiredoxins; Phosphorylation; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Signal Transduction; Transplantation, Heterologous

Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin 1 (MFN1) by SCFβ-TrCP E3 ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1. Importantly, MLN4924-induced mitochondrial fusion is independent of cell cycle progression, but confers cellular survival. Mass-spectrometry-based metabolic profiling and mitochondrial functional assays reveal that MLN4924 inhibits the TCA cycle but promotes mitochondrial OXPHOS. MLN4924 also increases glycolysis by activating PKM2 via promoting its tetramerization. Biologically, MLN4924 coupled with the OXPHOS inhibitor metformin, or the glycolysis inhibitor shikonin, significantly inhibits cancer cell growth both in vitro and in vivo. Together, our study links neddylation modification and energy metabolism, and provides sound strategies for effective combined cancer therapies.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclopentanes; Energy Metabolism; Female; GTP Phosphohydrolases; HEK293 Cells; Humans; Metformin; Mice; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Naphthoquinones; Neoplasms; Oxidative Phosphorylation; Proteolysis; Pyrimidines; Ubiquitin-Activating Enzymes; Ubiquitination; Xenograft Model Antitumor Assays

CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, the compounds induced differentiation, accompanied by decreased stemness properties, in intestinal crypt stem cell-derived Apc/K-Ras-mutant mouse organoids, and led to tumor regression and reduction of metastatic potential in zebrafish embryo xenografts used as in vivo model.

Topics: Adenomatous Polyposis Coli Protein; Animals; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Cycle; Cell Cycle Checkpoints; Cell Division; Crystallography, X-Ray; Enzyme Inhibitors; Heterografts; Humans; Mice; Mitosis; Molecular Docking Simulation; Naphthoquinones; Neoplasms; Protein Conformation

Remodeling tumor immune microenvironment (TIME) is an important strategy to lift the immunosuppression and achieve immune normalization. In this work, a mannosylated lactoferrin nanoparticulate system (Man-LF NPs) is developed for dual-targeting biomimetic codelivery of shikonin and JQ1 via the mannose receptor and LRP-1 that are overexpressed in both cancer cells and tumor-associated macrophages. The Man-LF NPs can serve as multitarget therapy for inducing immune cell death in the cancer cells, repressing glucose metabolism and repolarizing tumor-associated macrophages, and consequently, lead to remodeling the TIME (e.g., promotion of dendritic cell maturation and CD8

Topics: Azepines; Biomimetics; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Dendritic Cells; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Lactoferrin; Lectins, C-Type; Low Density Lipoprotein Receptor-Related Protein-1; Macrophages; Mannose; Mannose Receptor; Mannose-Binding Lectins; Nanoparticles; Naphthoquinones; Neoplasms; Receptors, Cell Surface; Triazoles; Tumor Microenvironment

Myeloid-derived suppressor cells (MDSCs) contribute to immune activity suppression and promote the tumor progression. Elimination of MDSCs is a promising cancer therapeutic strategy, and some chemotherapeutic agents have been reported to hamper tumor progression by suppressing MDSCs. Juglone has been showed to exert a direct cytotoxic effect on tumor cells. However, the effect of juglone on MDSCs and anti-tumor immune statue has remained unexplored. In our study, we observed that juglone suppressed tumor growth and metastasis markedly, and the tumor growth suppression in immunocompetent mice was more drastic than that in immunodeficient mice. Juglone reduced the accumulation of MDSCs and increased IFN-γ production by CD8

Topics: Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Fluorouracil; Interferon-gamma; Interleukin-1beta; Liver; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Myeloid-Derived Suppressor Cells; Naphthoquinones; Neoplasms

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI

Topics: Amides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Naphthoquinones; Neoplasms; Podophyllotoxin; Pyridines; Quinolines; rho-Associated Kinases; Stilbenes; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tubulin; Tubulin Modulators

AKT, also known as protein kinase B (PKB), is an established therapeutic target in cancer and its inhibitors are increasingly designed. The anti-cancer potential of a compound class naphthoquinones has been constantly realized. The current work aimed to explore AKT1 inhibitors from 1,4-naphthoquionone derivatives.. A library of 1,4-naphthoquionone derivatives was formed using similarity search and visual analysis. The library was used for virtual screening using molecular docking. For the screened compounds, the detailed binding pose analysis, binding energy and dissociation constant calculations were performed.. The top 10 screened compounds were proposed as potential AKT1 inhibitors with anti-cancer activity. The compounds were checked for any reported activity, and our 2nd rank compound was reported to have anti-cancer activity.. Our study proposes 10 compounds as potential AKT1 inhibitors and anticancer agents and also provides insights into their binding. This study also proposes AKT1 as a potential target of the reported anticancer compound, CID: 341807.

Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Naphthoquinones; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction

Plumbagin (PLB) is an active secondary metabolite extracted from the roots of Plumbago rosea. In this study, we report that plumbagin effectively induces paraptosis by triggering extensive cytoplasmic vacuolation followed by cell death in triple negative breast cancer cells (MDA-MB-231), cervical cancer cells (HeLa) and non-small lung cancer cells (A549) but not in normal lung fibroblast cells (WI-38). The vacuoles originated from the dilation of the endoplasmic reticulum (ER) and were found to be empty. The cell death induced by plumbagin was neither apoptotic nor autophagic. Plumbagin induced ER stress mainly by inhibiting the chymotrypsin-like activity of 26S proteasome as also evident from the accumulation of polyubiquitinated proteins. The vacuolation and cell death were found to be independent of reactive oxygen species generation but was effectively inhibited by thiol antioxidant suggesting that plumbagin could modify the sulfur homeostasis in the cellular milieu. Plumbagin also resulted in a decrease in mitochondrial membrane potential eventually decreasing the ATP production. This is the first study to show that Plumbagin induces paraptosis through proteasome inhibition and disruption of sulfhydryl homeostasis and thus further opens up the lead molecule to potential therapeutic strategies for apoptosis-resistant cancers.

Topics: Cell Death; Cell Line; Cell Line, Tumor; Endoplasmic Reticulum Stress; Homeostasis; Humans; Membrane Potential, Mitochondrial; Naphthoquinones; Neoplasms; Proteasome Inhibitors; Sulfhydryl Compounds; Vacuoles

Topics: A549 Cells; Animals; Cell Line, Tumor; Humans; Immunity, Innate; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Neoplasms, Experimental; Prodrugs; Reactive Oxygen Species; Signal Transduction; T-Lymphocytes; Xenograft Model Antitumor Assays

Many cancer cells undergo metabolic reprogramming known as the Warburg effect, which is characterized by a greater dependence on glycolysis for ATP generation, even under normoxic conditions. Glyoxalase I (GLO I) is a rate-limiting enzyme involved in the detoxification of cytotoxic methylglyoxal formed in glycolysis and which is known to be highly expressed in many cancer cells. Thus, specific inhibitors of GLO I are expected to be effective anticancer drugs. We previously discovered a novel GLO I inhibitor named TLSC702. Although the strong inhibitory activity of TLSC702 was observed in the in vitro enzyme assay, higher concentrations were required to induce apoptosis at the cellular level. One of the proposed reasons for this difference is that cancer cells alter the energy metabolism leading them to become more dependent on mitochondrial respiration than glycolysis (Metabolic shift) to avoid apoptosis induction. Thus, we assumed that combination of TLSC702 with shikonin-a specific inhibitor of pyruvate kinase M2 (PKM2) that acts as a driver of TCA cycle by supplying pyruvate and which is known to be specifically expressed in cancer cells-would have anticancer effects. We herein show the anticancer effects of combination treatment with TLSC702 and shikonin, and a possible anticancer mechanism.

Topics: Apoptosis; Butyrates; Carrier Proteins; Cell Line, Tumor; Citric Acid Cycle; Drug Screening Assays, Antitumor; Humans; Lactoylglutathione Lyase; Membrane Proteins; Naphthoquinones; Neoplasm Proteins; Neoplasms; Pyruvate Kinase; Pyruvic Acid; Thiazoles; Thyroid Hormone-Binding Proteins; Thyroid Hormones

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Drug Design; Glycolysis; HeLa Cells; Humans; Mitosis; Naphthoquinones; Neoplasms; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Tubulin; Tubulin Modulators

Cytotoxic activities of acetylshikonin and acetoxyisovalerylshikonin alone and in combination with chemotherapeutic agents against parental and drug resistant cell lines were determined using the MTT assay. Effects of Shikonin derivatives on BCRP, MDR1 and MRP transcript and protein levels were relatively measured. Finally, accumulation and efflux kinetics were conducted. The results revealed cell- and concentration-dependency of the cell cytotoxicity. Acetylshikonin and acetoxyisovalerylshikonin transiently made the mRNA ocean turbulent, but FACS analyses using fluorescent-labeled antibodies showed no significant change in the MDR-protein levels. Functional kinetics revealed significant block of MDR1, BCRP and MRP transporter in the presence of shikonin derivatives. Maximum accumulation fold changes was quantified to be 4.4 and consequently, acetoxyisovalerylshikonin pretreated EPG85.257RDB cells was chemosensitized to daunorubicin tension 3.1-fold. Although, the MDR blockage was reported to follow time- and cell-dependent patterns, MDR1, BCRP and MRP2 responses to the shikonins are concentration-independent. These data suggest uncompetitive transporter blockage behavior of these agents. The results indicated that shikonin derivatives stimulate uptake and reduce efflux of chemotherapeutic agents in the malignant cancer cells, suggesting that chemotherapy in combination with shikonin compounds may be beneficial to cancer cells that overexpress multidrug resistance transporters.

Topics: Anthraquinones; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Multidrug Resistance-Associated Proteins; Naphthoquinones; Neoplasm Proteins; Neoplasms; Phenotype

STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and cancer stemness properties, can inhibit stemness gene expression and kill stemness-high cancer cells isolated from a variety of cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC

Topics: Antineoplastic Agents; Benzofurans; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Molecular Docking Simulation; Naphthoquinones; Neoplasms; Neoplastic Stem Cells; STAT3 Transcription Factor

Morita-Baylis-Hillman acetates and α-bromonitroalkenes have been employed in cascade reactions with lawsone and 2-aminonaphthoquinone for the one-pot synthesis of heterocycle fused quinonoid compounds. The reactions reported here utilized the 1,3-binucleophilic potential of hydroxy- and aminonaphthoquinones and the 1,2/1,3-bielectrophilic potential of bromonitroalkenes and Morita-Baylis-Hillman acetates for the synthesis of pyrrole and furan fused naphthoquinones. The synthesized compounds were evaluated against HCT-116 (human colon carcinoma cells), PC3 (human prostate cancer cells), HL-60 (human promyelocytic leukemia cells), SF295 (human glioblastoma cells) and NCI-H460 (human lung cancer cells) and exhibited antitumor activity with IC

Topics: Acetates; Alkenes; Amination; Antineoplastic Agents; Cell Line, Tumor; Chemistry Techniques, Synthetic; Furans; Halogenation; Humans; Models, Molecular; Naphthoquinones; Neoplasms; Pyrroles; Quinones; Structure-Activity Relationship

Xiakemycin A (XKA), a new pyranonaphthoquinone antibiotic, is isolated from the fermentation broth of Streptomyces sp. CC8-201. It exerts potent suppression of cell proliferation on some types of tumor cells. In the present study, its underlying mechanism on tumor cells has been investigated. In contrast to the specific AKT inhibitor triciribine hydrate, XKA demonstrated a weak inhibition of the AKT kinase activity in vitro. Knockdown of AKT protein levels reduced XKA-inhibitory action on prostate carcinoma PC-3 cells. Degradation of AKT protein was markedly observed in the XKA-treated PC-3 cells in comparison with triciribine hydrate treatment. There was no typical apoptosis induced by XKA in PC-3 cells. The propidium iodide-stained cells increased concentration-dependently when the cells were treated with XKA. Degradation of apoptosis-related proteins, such as p53 and PARP-1, was also detected in the XKA-treated PC-3 cells. Knockdown of p53 protein levels potentiated XKA action on non-small lung cancer A549 cells. Collectively, the mechanism of XKA potent inhibition was due to degradation of AKT protein and low endogenous p53 levels. As a leading compound, new derivatives based on XKA will be developed to precisely treat tumor cells which have high AKT and low p53 protein levels.

Topics: A549 Cells; Acenaphthenes; Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HeLa Cells; Hep G2 Cells; Humans; Male; MCF-7 Cells; Naphthoquinones; Neoplasms; Phosphorylation; Proteolysis; Proto-Oncogene Proteins c-akt; Ribonucleotides; Tumor Suppressor Protein p53

Topics: Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B; Caco-2 Cells; Cell Proliferation; Cell Survival; Coumarins; Down-Regulation; Drug Synergism; Gene Expression Regulation, Neoplastic; HeLa Cells; Hep G2 Cells; Humans; In Vitro Techniques; Malvaceae; MCF-7 Cells; Molecular Structure; Naphthoquinones; Neoplasms; Paclitaxel; Plant Extracts

Naphthoquinones and 1,2,3-triazoles are structural pharmacophore that is known to impart several cancer cells. This work shows a synthetic methodology to obtain hybrid molecules involving naphthoquinone and triazol scaffold as multiple ligands. A simple and efficient synthetic route was used to prepare a series of sixteen compounds being eight 2-(1-aryl-1H-1,2,3-triazol-4-yl)-2,3-dihydronaphtho[1,2 b]furan-4,5-diones and eight 2-(1-aryl-1H-1,2,3-triazol-4-yl)-2,3-dihydronaphtho[2,3-b]furan-4,9-diones. These compounds were tested in MDA-MB231, Caco-2 and Calu-3 human cancer cells, and among them 7a was the most selective compound on Caco-2 cells, the most sensitized cell line in this study. In silico study suggest that the blockage of topoisomerase I and IIα may be one of the mechanisms of action responsible for the cytotoxic effect of 7a in Caco-2 cells.

Topics: Antineoplastic Agents; Caco-2 Cells; Cell Line, Tumor; Cell Survival; DNA Topoisomerases, Type I; Humans; Models, Molecular; Naphthoquinones; Neoplasms; Structure-Activity Relationship; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Triazoles

Phytochemicals like Lawsone have some drawbacks that stem from their poor solubility. Low solubility in aqueous mediums results in low bioavailability, poor permeability and instability of phytochemical compounds in biological environments. The aim of this study was to design nanoniosomes containing Lawsone (Law) using non-ionic surfactants and cholesterol. Niosomes were prepared by thin film hydration method (TFH). Then, they were loaded with Henna extract (HLaw) and standard Lawsone (SLaw), and two resulted formulations were compared. The henna extract was analyzed by mass gas chromatography. Size, zeta potential, polydispersity index (PDI) and morphology of the loaded formulations were evaluated by dynamic light scattering (DLS) and scanning electron spectroscopy (SEM). The incorporation and release rate of Law from niosome bilayers were evaluated by UV-Vis spectroscopy. In vitro experiments were carried out to evaluate antitumor activity in MCF-7 cell line. The results showed distinct spherical shapes and particle sizes were about 250 nm in diameter and have negative zeta potentials. Niosomes were stable at 4 °C for 2 months. Entrapment efficiently of both formulations was about 70% and showed a sustained release profile. In vitro study exhibited that using of niosome to encapsulating Law can significantly increase antitumor activity of formulation in MCF-7 cell line compared to Law solution (free Law). Thus, niosomes are a promising carrier system for delivery of phytochemical compounds that have poor solubility in biological fluids. Graphical abstract ᅟ.

Topics: Cell Line, Tumor; Cell Survival; Cholesterol; Drug Compounding; Drug Liberation; Drug Stability; Humans; Lawsonia Plant; Liposomes; Naphthoquinones; Neoplasms; Particle Size; Plant Extracts; Surface Properties; Surface-Active Agents

Hyperthermia (HT) has been used widely for cancer therapy, and the development of modern devices has made it more efficient. Shikonin (SHK) is a natural naphthoquinone derivative from a Chinese herb. Although the anticancer properties of SHK are evident, the underlying molecular mechanisms are not fully understood.. In this study, the effects of combining low doses of SHK with mild HT were investigated in the U937 cell line.. The cells were subjected to HT at 44°C for 10 min with or without SHK pretreatment, and parameters reflecting apoptosis, ROS generation and intracellular calcium elevation were evaluated by using DNA fragmentation, flow cytometry, and western blot analyses.. SHK 0.5 µM significantly enhanced HT-induced apoptosis as indicated by DNA fragmentation and caspase-3 activation with increased generation of ROS and elevation of intracellular calcium. The combined treatment also synergistically activated proapoptotic proteins and inactivated anti-apoptotic proteins. Furthermore, the phosphorylation of JNK and PKC- δ and the dephosphorylation of ERK and AKT were the upstream effects that may have compounded the induction of apoptosis. The modulatory effects of HT and SHK were abrogated with the employment of NAC and JNK-IN-8 by inactivating the MAPK pathway and cleavage of caspase-3. Intracellular calcium was also elevated and was found to be responsible for the induction of cell death evident by the DNA fragmentation with or without the employment of BAPTA-AM.. Conclusively, this study provides persuasive evidence that SHK in combination with HT is a propitious therapeutic way for augmentation of apoptosis and hence suggest a novel strategy for treating cancers.

Topics: Apoptosis; Humans; Hyperthermia, Induced; Naphthoquinones; Neoplasm Proteins; Neoplasms; Oxidative Stress; Reactive Oxygen Species; U937 Cells

Doxorubicin, an anthracycline from

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiotonic Agents; Cardiotoxicity; Cell Survival; Doxorubicin; Female; Glutathione; HeLa Cells; Humans; MCF-7 Cells; Membrane Potential, Mitochondrial; Metabolomics; Mitochondria; Myocytes, Cardiac; Naphthoquinones; Neoplasms; Nuclear Magnetic Resonance, Biomolecular; Oxidative Stress; Proteomics; Proton Magnetic Resonance Spectroscopy; Rats; Reactive Oxygen Species; Sea Urchins

Hypoxia enhances the development of solid tumors. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that is dominantly expressed under hypoxia in solid tumor cells and is a key factor of tumor regulation. HIF-1α regulates several target genes involved in many aspects of cancer progression, including angiogenesis, metastasis, and cell proliferation, as well as imparting resistance to cancer treatment. In this study, we assessed shikonin, which derives from the traditional medical herb Lithospermum erythrorhizon, for its anti-cancer effects in hypoxia-induced human colon cancer cell lines. Shikonin showed potent inhibitory activity against hypoxia-induced HIF-1α activation in various human cancer cell lines and efficient scavenging activity of hypoxia-induced reactive oxygen species in tumor cells. Further analysis revealed that shikonin inhibited HIF-1α protein synthesis without affecting the expression of HIF-1α mRNA or degrading HIF-1α protein. It was subsequently shown to attenuate the activation of downstream mTOR/p70S6K/4E-BP1/eIF4E kinase. Shikonin also dose-dependently caused the cell cycle arrest of activated HCT116 cells and inhibited the proliferation of HCT116 and SW620 cells. Moreover, it significantly inhibited tumor growth in a xenograft modal. These findings suggest that shikonin could be considered for use as a potential drug in human colon cancer therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; HCT116 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lithospermum; Mice; Mice, Inbred BALB C; Mice, Nude; Naphthoquinones; Neoplasms; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Transplantation, Heterologous

New Ru(II) complexes with lawsone (law) characterized as trans-[Ru(law)(PPh

Topics: A549 Cells; Antineoplastic Agents; Coordination Complexes; G1 Phase; Humans; Naphthoquinones; Neoplasms; Ruthenium; S Phase

ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2, and Bcl-w, and it has been reported for anti-cancer effects in various types of cancer cells. However, ABT-737 fails to induce apoptosis in cancer cell with high levels of Mcl-1 expression. The pharmacological survivin inhibitor YM155 has been reported to induce downregulation of Mcl-1 expression. Therefore, we investigated the effect of YM155 to sensitize resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. We found that ABT-737 alone and YM155 alone did not induce apoptosis, but YM155 markedly sensitized ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma cells (U251MG), and human lung carcinoma cells (A549). In contrast, combined treatment with ABT-737 and YM155 did not increase apoptosis in normal mouse kidney cells (TCMK-1) and human mesangial cells (MC). YM155 induced lysosome-dependent downregulation of Mcl-1 expression in Mcl-1-overexpressed Caki cells. In addition, combined treatment with ABT-737 and YM155 induced loss of mitochondrial membrane potential and inhibited interaction of Bcl-xL and Bax. Taken together, our results suggested that YM155 effectively improves sensitivity to ABT-737 through downregulation of Mcl-1 expression.

Topics: A549 Cells; Animals; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Membrane Potential, Mitochondrial; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Naphthoquinones; Neoplasms; Nitrophenols; Piperazines; Sulfonamides

Biflorin 1 is a biologically active quinone, isolated from Capraria biflora. Five new biflorin-based nitrogen derivatives were synthesized, of which two were mixtures of (E)- and (Z)- isomers: (Z)-2a, (Z)-2b, (Z)-3a, (Z)- and (E)-3b, (Z)- and (E)-3c. The antibacterial activity was investigated using the microdilution method for determining the minimum inhibitory concentration (MIC) against six bacterial strains. Tests have shown that these derivatives have potential against all bacterial strains. The cytotoxic activity was also evaluated against three strains of cancer cells, but none of the derivatives showed activity.

Topics: Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Bacteria; Bacterial Infections; Cell Line, Tumor; Humans; Hydrazones; Microbial Sensitivity Tests; Naphthoquinones; Neoplasms; Oximes; Scrophulariaceae

An efficient and regioselective synthetic route to naphthoquinone/naphthoquinol-carbohydrate hybrids has been developed. It is based upon anionic annulation of 3-nucleofugalphthalides with an acrylate appended sugar moiety. In each of the annulations studied, the arene-carbohydrate hybrids were obtained in good to excellent yields. The in vitro cytotoxic activity of the synthetic naphthoquinone/naphthonol-carbohydrate hybrids were evaluated against the human cervical cancer cell line (HeLa), and a few of them were found to exhibit potent anticancer activity against the cell line.

Topics: Anions; Antineoplastic Agents; Carbohydrates; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Naphthoquinones; Neoplasms

The spatial-temporal synchronization of photothermal therapy and chemotherapy is highly desirable for an efficient cancer treatment with synergistic effect. Herein, we developed a chemotherapeutic drug doxorubicin (DOX) and photothermal conjugated polymer (CP) co-loaded nanoplatform using a near-infrared (NIR) laser responsive amphiphilic brush copolymer as the encapsulation matrix. The obtained nanoparticles (NPs) exhibit good monodispersity and excellent stability, which can efficiently convert laser energy into thermal energy for photothermal therapy. Moreover, the hydrophobic polymer matrix bearing a number of 2-diazo-1,2-naphthoquinones (DNQ) moieties could be transformed to a hydrophilic one upon NIR two-photon laser irradiation, which leads to fast drug release. Furthermore, the surface modification of the NPs with cyclic arginine-glycine-aspartic acid (cRGD) tripeptide significantly enhances the accumulation of the NPs within integrin αvβ3 overexpressed cancer cells. The half-maximal inhibitory concentration (IC50) of the combination therapy is 13.7 μg mL(-1), while the IC50 for chemotherapy and photothermal therapy alone is 147.8 μg mL(-1) and 36.2 μg mL(-1), respectively. The combination index (C.I.) is 0.48 (<1), which indicates the synergistic effect for chemotherapy and PTT. These findings provide an excellent NIR laser regulated nanoplatform for combined cancer treatment with synergistic effect due to the synchronous chemo- and photo-thermal therapy.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Nucleus; Combined Modality Therapy; Doxorubicin; Drug Carriers; Drug Delivery Systems; Female; HEK293 Cells; Humans; Hyperthermia, Induced; Inhibitory Concentration 50; Integrin alphaVbeta3; Lactic Acid; Lasers; Magnetic Resonance Spectroscopy; MCF-7 Cells; Microscopy, Confocal; Nanoparticles; Nanotechnology; Naphthoquinones; Neoplasms; Oligopeptides; Photochemotherapy; Photons; Polyesters; Polymers; Spectroscopy, Near-Infrared

Four new meroterpenoids, arnebinols A-D (1-4), and one new prenylated naphthoquinone, 5,8-O-dimethyl-11-deoxyalkannin (5), together with seven known meroterpenoids (6-12) were isolated from the roots of Arnebia euchroma. The structures of the isolated compounds were elucidated unambiguously by spectroscopic data analysis, as well as X-ray-single crystal diffraction analysis. Arnebinol A (1) and B (2) are rare meroterpenoids possessing a 6/10/5 tricyclic ring system. Compounds 1-12 were evaluated for their cytotoxicities against MG-63 and SNU387 human cancer cell lines. Compound 5 exhibited the most potent activity with IC50 values of 2.69 µM and 6.08 µM, respectively.

Topics: Antineoplastic Agents, Phytogenic; Boraginaceae; Cell Line, Tumor; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Molecular Structure; Monoterpenes; Naphthoquinones; Neoplasms; Phytotherapy; Plant Extracts; Plant Roots; Prenylation; Terpenes

To examine the effect of hydrophobicity on the anticancer activity of 1,4-naphthoquinone derivatives, a series of compounds bearing a 2-O-alkyl-, 3-C-alkyl- or 2/3-N-morpholinoalkyl group were synthesized and evaluated for their anticancer activity against five human cancer cell lines in vitro. The cytotoxicity of these derivatives was assayed against HT-29, SW480, HepG2, MCF-7 and HL-60 cells by the MTT assay. Among them, 2-hydroxy-3-farnesyl-1,4-naphthoquinone (11a) was found to be the most cytotoxic against these cell lines. Our results showed that the effectiveness of compound 11a may be attributed to its suppression of the survival of HT-29. Secondly, in the Hoechst 33258 staining test, compound 11a-treated cells exhibited nuclear condensation typical of apoptosis. Additionally, cell cycle analysis by flow cytometry indicated that compound 11a arrested HT-29 cells in the S phase. Furthermore, cell death detected by Annexin V-FITC/propidium iodide staining showed that compound 11a efficiently induced apoptosis of HT-29 in a concentration-dependent manner. Taken together, compound 11a effectively inhibits colon cancer cell proliferation and may be a potent anticancer agent.

Topics: Cell Cycle; Cell Line, Tumor; Flow Cytometry; Humans; Lipids; Naphthoquinones; Neoplasms

Mitochondria play important roles in tumor cell physiology and survival by providing energy and metabolites for proliferation and metastasis. As part of their oncogenic status, cancer cells frequently produce increased levels of mitochondrial-generated reactive oxygen species (ROS). However, extensive stimulation of ROS generation in mitochondria has been shown to be able to induce cancer cell death, and is one of the major mechanisms of action of many anticancer agents. We hypothesized that enhancing mitochondrial ROS generation through direct targeting of a ROS generator into mitochondria will exhibit tumor cell selectivity, as well as high efficacy in inducing cancer cell death. We thus synthesized a mitochondrial targeted version of β-lapachone (XJB-Lapachone) based on our XJB mitochondrial targeting platform. We found that the mitochondrial targeted β-lapachone is more efficient in inducing apoptosis compared to unconjugated β-lapachone, and the tumor cell selectivity is maintained. XJB-Lapachone also induced extensive cellular vacuolization and autophagy at a concentration not observed with unconjugated β-lapachone. Through characterization of mitochondrial function we revealed that XJB-Lapachone is indeed more capable of stimulating ROS generation in mitochondria, which led to a dramatic mitochondrial uncoupling and autophagic degradation of mitochondria. Taken together, we have demonstrated that targeting β-lapachone accomplishes higher efficacy through inducing ROS generation directly in mitochondria, resulting in extensive mitochondrial and cellular damage. XJB-Lapachone will thus help to establish a novel platform for the design of next generation mitochondrial targeted ROS generators for cancer therapy.

Topics: Apoptosis; Cell Death; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Humans; Mitochondria; Molecular Structure; Naphthoquinones; Neoplasms; Reactive Oxygen Species; Structure-Activity Relationship; Vacuoles

Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine.

Topics: Adult; Animals; Autophagy; Cancer Vaccines; Cell Differentiation; Cell Line, Tumor; Dendritic Cells; Female; Humans; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Middle Aged; Naphthoquinones; Neoplasm Metastasis; Neoplasms; Sirolimus; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Young Adult

Biflorin is an o-naphthoquinone isolated from the roots of the plant Capraria biflora L. (Scrophulariaceae). In this study, the cytotoxic effects of biflorin were verified, and late apoptosis was detected in various cancer cell lines by in situ analysis. The cytotoxicity was further evaluated exclusively for 48 h of treatment in different tumor and non-tumor cell lines (Hep-2, HeLa, HT-29, A-375, and A-549, and HEK-293, respectively). The results indicated that biflorin induced selective cytotoxicity in tumor cells. HeLa cells were more susceptible to biflorin, followed by HT-29, A-549, A-375, and Hep-2 at all concentrations (range 5-50 μg/mL), and the highest half-maximal inhibitory concentration IC50 (56.01 ± 1.17 μg/mL) was observed in HEK-293 cells. Late apoptotic/necrotic events, observed by in situ immunostaining with Annexin V, varied with each cell line; an increase in late apoptotic events was observed corresponding to the increase in biflorin dosage. Hep-2 cells showed a greater percentage of late apoptotic events among the tumor cell lines when treated with higher concentrations of biflorin (69.63 ± 2.28%). The non-tumor HEK-293 line showed greater resistance to late apoptotic events, as well as a lower level of cytotoxicity (77.69 ± 6.68%) than the tested tumor lines. The data presented indicate that biflorin showed an important, possibly selective, cytotoxicity against tumor cell lines, thereby revealing a promising novel substance with potential anticancer activity for tumor therapy.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; HEK293 Cells; Humans; Naphthoquinones; Neoplasms; Scrophulariaceae

A series of 17 selected natural and semisynthetic 1,4-naphthoquinones were synthesized, and their growth inhibitory activity was evaluated in vitro. The compounds were tested on six human cancer cell lines using the MTT colorimetric assay. The data revealed that of the chemicals under study only lapachol, its acetate and 3-geranyllawsone displayed the highest activity, recording mean IC50 values ranging from 15 to 22 μM.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colorimetry; Growth Inhibitors; Humans; Naphthoquinones; Neoplasms; Plant Extracts

Cancer is a major public health burden in both developed and developing countries. The quinone moiety has been shown to possess antitumor activity and several cancer drugs in clinical use contain this entity. The effect of isofuranonaphthoquinone isolated from Bulbine frutescens on Jurkat T cells was determined. Cells were exposed to the isofuranonaphthoquinone (IFNQ) at different concentrations. Significant antiproliferative effects were observed which were comparable to that of the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). A combination of IFNQ with BCNU produced synergistic effects which were observed after 72 hrs. It was also observed that combining IFNQ with reduced glutathione abolished the anticancer activity of the compound. It is, therefore, proposed that the isofuranonaphthoquinone may exert part of its effect by producing reactive oxygen species resulting in death of the cells as the effects of this compound were antagonized by reduced glutathione. An investigation on the effects of isofuranonaphthoquinone on glutathione transferase (GST) activity and drug efflux pumps showed that this compound exhibited inhibitory effects on both the GST and the drug efflux pumping activities. Thus, the isofuranonaphthoquinone showed cytotoxicity, works through inhibition of some cellular mechanisms, and could present a potential source of lead compounds for anticancer drug development.

Topics: Cell Proliferation; Cell Survival; Humans; Jurkat Cells; Liliaceae; Naphthoquinones; Neoplasms; Plant Extracts

Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, has been shown to exert anti-cancer and anti-proliferative activities in vitro as well as in animal tumor models. However, the mechanism underlying its anti-tumor action still remains unclear. CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors whose function is altered in cancer due to increased expression and overactive transport. We showed that CRM1 is a direct cellular target of plumbagin. The nuclei of cells incubated with plumbagin accumulated tumor-suppressor proteins and inhibited the interactions between CRM1 and these proteins. Particularly, we demonstrated that plumbagin could specifically react with the conserved Cys(528) of CRM1 but not with a Cys(528) mutant peptide through Mass spectrometric analysis. More importantly, cancer cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of plumbagin, demonstrating that the inhibition is through direct interaction with Cys(528) of CRM1. The inhibition of nuclear traffic by plumbagin may account for its therapeutic properties in cancer and inflammatory diseases. Our findings could contribute to the development of a new class of CRM1 inhibitors.

Topics: Cell Line, Tumor; Cell Nucleus; Drug Design; Exportin 1 Protein; Humans; Karyopherins; Molecular Targeted Therapy; Naphthoquinones; Neoplasms; Nuclear Proteins; Phytotherapy; Plumbaginaceae; Protein Transport; Receptors, Cytoplasmic and Nuclear; Tumor Suppressor Proteins

The molecular structure, vibrational analysis and molecular docking analysis of the 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate (MDDNAB) molecule have been carried out using FT-IR and FT-Raman spectroscopic techniques and DFT method. The equilibrium geometry, harmonic vibrational wave numbers, various bonding features have been computed using density functional method. The calculated molecular geometry has been compared with experimental data. The detailed interpretation of the vibrational spectra has been carried out by using VEDA program. The hyper-conjugative interactions and charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The simulated FT-IR and FT-Raman spectra satisfactorily coincide with the experimental spectra. The PES and charge analysis have been made. The molecular docking was done to identify the binding energy and the Hydrogen bonding with the cancer protein molecule.

Topics: Crystallization; Hydrogen Bonding; Molecular Conformation; Molecular Docking Simulation; Naphthoquinones; Neoplasms; para-Aminobenzoates; Spectrophotometry, Infrared; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Vibration

To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core-scaffold-modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R-, S-, and 2- and 6-isomers) were synthesized in high enantiomeric excess (>99 % ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor-inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells.

Topics: Alkylation; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Design; Female; Male; Mice; Microsomes, Liver; Naphthoquinones; Neoplasms; Prodrugs; Rats; Reactive Oxygen Species; Stereoisomerism; Structure-Activity Relationship; Transplantation, Heterologous; Transplantation, Homologous

Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by. quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16-F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16-F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ~80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16-F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells.

Topics: Activation, Metabolic; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Electron Transport Complex I; Enzyme Inhibitors; Humans; Indolequinones; Mice; Mitochondria; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasm Proteins; Neoplasms; Oxidation-Reduction; Prodrugs; Reactive Oxygen Species; Reverse Transcriptase Inhibitors; Rotenone

Three new napyradiomycins (1-3) were isolated from the culture broth of a marine-derived actinomycete strain SCSIO 10428, together with six known related analogues napyradiomycin A1 (4), 18-oxonapyradiomycin A1 (5), napyradiomycin B1 (6), napyradiomycin B3 (7), naphthomevalin (8), and napyradiomycin SR (9). The strain SCSIO 10428 was identified as a Streptomyces species by the sequence analysis of its 16S rRNA gene. The structures of new compounds 1-3, designated 4-dehydro-4a-dechlorona pyradiomycin A1 (1), 3-dechloro-3-bromonapyradiomycin A1 (2), and 3-chloro-6, 8-dihydroxy-8-α-lapachone (3), respectively, were elucidated by comparing their 1D and 2D NMR spectroscopic data with known congeners. None of the napyradiomycins 1-9 showed antioxidative activities. Napyradiomycins 1-8 displayed antibacterial activities against three Gram-positive bacteria Staphylococcus and Bacillus strains with MIC values ranging from 0.25 to 32 μg mL⁻¹, with the exception that compound 3 had a MIC value of above 128 μg mL⁻¹ against Staphylococcus aureus ATCC 29213. Napyradiomycins 2, 4, 6, and 7 exhibited moderate cytotoxicities against four human cancer cell lines SF-268, MCF-7, NCI-H460, and HepG-2 with IC₅₀ values below 20 μM, while the IC₅₀ values for other five napyradiomycins 1, 3, 5, 8 and 9 were above 20 μM.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Bacteria; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Naphthoquinones; Neoplasms; Streptomyces

Three-component coupling of aldehyde, 2-hydroxy-1,4-naphthoquinone and 3-amino-1,2,4-triazole has been achieved using a catalytic amount of sulfamic acid under solvent free conditions to produce a novel series of 6-aryl-benzo[h][1,2,4]-triazolo[5,1-b]quinazoline-7,8-dione derivatives in good yields and with high regioselectivity. These compounds are found to exhibit potent antitumoral properties.

Topics: Aldehydes; Antineoplastic Agents; Catalysis; Cell Line, Tumor; Hep G2 Cells; Humans; Naphthoquinones; Neoplasms; Quinazolines; Sulfonic Acids; Triazoles

Peroxiredoxin (Prx) 1 is a member of the thiol-specific peroxidases family and plays diverse roles such as H2O2 scavenger, redox signal transducer and molecular chaperone. Prx1 has been reported to be involved in protecting cancer cells against various therapeutic challenges. We investigated how modulations of intracellular redox system affect cancer cell sensitivity to reactive oxygen species (ROS)-generating drugs. We observed that stable and transient Prx1 knockdown significantly enhanced HeLa cell sensitivity to β-lapachone (β-lap), a potential anticancer agent. Prx1 knockdown markedly potentiated 2 µM β-lap-induced cytotoxicity through ROS accumulation. This effect was largely NAD(P)H:quinone oxidoreductase 1 dependent and associated with a decrease in poly(ADP-ribose) polymerase 1 protein levels, phosphorylation of JNK, p38 and Erk proteins in mitogen-activated protein kinase (MAPK) pathways and a decrease in thioredoxin 1 (Trx1) protein levels. Trx1 serves as an electron donor for Prx1 and is overexpressed in Prx1 knockdown cells. Based on the fact that Prx1 is a major ROS scavenger and a partner of at least ASK1 and JNK, two key components of MAPK pathways, we propose that Prx1 knockdown-induced sensitization to β-lap is achieved through combined action of accumulation of ROS and enhancement of MAPK pathway activation, leading to cell apoptosis. These data support the view that modulation of intracellular redox state could be an alternative approach to enhance cancer cell sensitivity to ROS-generating drugs or to overcome some types of drug resistance.

Topics: Apoptosis; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; HeLa Cells; Humans; Hydrogen Peroxide; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; p38 Mitogen-Activated Protein Kinases; Peroxiredoxins; Phosphorylation; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Reverse Transcriptase Inhibitors; RNA Interference; RNA, Small Interfering; Thioredoxins

Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance.. Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling.. After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of βII-tubulin, which physically interacted with shikonin.. Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance.

Topics: Antineoplastic Agents; Cell Proliferation; Cisplatin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; K562 Cells; MCF-7 Cells; Naphthoquinones; Neoplasms; Paclitaxel; Time Factors

Angiogenesis-based therapy is an effective anti-tumour strategy and previous reports have shown some beneficial effects of a naturally occurring bioactive compound plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone). Here, we sought to determine the biological effects of plumbagin on signalling mechanisms during tumour angiogenesis.. The effects of plumbagin were evaluated in various in vitro assays which utilised human umbilical vein endothelial cells (HUVEC) proliferation, migration and tube formation. Plumbagin was also evaluated in vivo using chicken embryo chorioallantoic membrane (CAM) and mouse corneal micropocket models., Human colon carcinoma and prostate cancer xenograft mouse models were used to evaluate the effects of plumbagin on angiogenesis. Immunofluorescence, GST pull-down and Western blotting were employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated Ras signalling pathways.. Plumbagin not only inhibited endothelial cell proliferation, migration and tube formation but also suppressed chicken chorioallantoic membrane neovascularzation and VEGF-induced mouse corneal angiogenesis. Moreover, plumbagin suppressed tumour angiogenesis and tumour growth in human colon carcinoma and prostate cancer xenograft mouse models. At a molecular level, plumbagin blocked the Ras/Rac/cofilin and Ras/MEK signalling pathways mediated by VEGFR2 in HUVECs.. Plumbagin inhibited tumour angiogenesis and tumour growth by interference with the VEGFR2-mediated Ras signalling pathway in endothelial cells. Our findings demonstrate a molecular basis for the effects of plumbagin and suggest that this compound might have therapeutic ant-tumour effects.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chickens; Chorioallantoic Membrane; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Naphthoquinones; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; ras Proteins; Signal Transduction; Tumor Burden; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Sixteen novel naphthoquinone aromatic amides were synthesized by a new route starting from 1-hydroxy-2-naphthoic acid in nine or ten steps with good to excellent yield. Amide formation reaction was carried out by using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as an efficient condensing agent leading to carboxamides in high yield. The key step for converting naphthol to 3-hydroxynaphthoquinone was the Fremy's salt oxidation followed by hydroxylation with tert-butyl hydroperoxide and triton B. Anticancer activity of these new naphthoquinone amides were evaluated and benzamide 22 showed potent inhibition against NCI-H187 cell lines while naphthamides 23 and 43 were the most potent inhibition against KB cells. The decatenation assay revealed that compounds 24 and 43 at 20 μM can inhibit hTopoIIα activity while three other compounds, namely compounds 22, 23, and 45, exhibited hTopoIIα inhibitory activity at final concentration of 50 μM. Docking experiment revealed the same trend as the cytotoxicity and decatenation assay. Therefore, naphthamides 24 and 43 can be promising target molecules for anticancer drug development.

Topics: Amides; Antigens, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; DNA Topoisomerases, Type II; DNA-Binding Proteins; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Naphthoquinones; Neoplasms; Structure-Activity Relationship

To establish whether NSC80467, a novel fused naphthquinone imidazolium, has a similar spectrum of activity to the well-characterized "survivin suppressant" YM155 and to extend mechanistic studies for this structural class of agent.. NSC80467 and YM155 were analyzed in parallel using assays measuring viability, survivin suppression, inhibition of DNA/RNA/protein synthesis and the cellular response to DNA damage.. GI(50) values generated for both compounds in the NCI-60 screen yielded a correlation coefficient of 0.748, suggesting significant concordance. Both agents were also shown to inhibit protein expression of survivin [BIRC5]. COMPARE analysis identified DNA damaging agents chromomycin A3 and bisantrene HCl and one DNA-directed inhibitor of transcription, actinomycin D, as correlating with the activity of NSC80467 and YM155. Furthermore, both agents were shown to preferentially inhibit DNA, over RNA and protein synthesis. Thus, the ability of NSC80467 and YM155 to induce a DNA damage response was examined further. Treatment of PC3 cells with either agent resulted in dose-dependent induction of γH2AX and pKAP1, two markers of DNA damage. The concentrations of agent required to stimulate γH2AX were considerably lower than those required to inhibit survivin, implicating DNA damage as an initiating event. The DNA damage response was then confirmed in a panel of cell lines treated with NSC80467 or YM155, suggesting that γH2AX and pKAP1 have potential as response biomarkers.. These data provide the first evidence that NSC80467 and YM155 are DNA damaging agents where suppression of survivin is a secondary event, likely a consequence of transcriptional repression.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; DNA Damage; DNA, Neoplasm; Dose-Response Relationship, Drug; HCT116 Cells; Histones; HT29 Cells; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; K562 Cells; Molecular Structure; Naphthoquinones; Neoplasms; Protein Biosynthesis; Repressor Proteins; RNA, Neoplasm; Survivin; Time Factors; Tripartite Motif-Containing Protein 28

Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+ /ATP depletion that stimulate Ca2+ -dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1- cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Calcium; Cell Line, Tumor; DNA Damage; Egtazic Acid; Humans; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Necrosis; Neoplasms; Oxidation-Reduction; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Quinones; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering

This work evaluated the potential of Pluronics (varieties F127 and P123) in combination with solubilizing agents to be used as syringeable in situ gelling depots of intratumoral β-lapachone (βLAP). Pluronic dispersions prepared at various concentrations in the absence and the presence of ethanol and randomly methylated β-cyclodextrin (RMβCD) were characterized regarding their rheological properties, drug solubilization capacity, and in vitro release. Pluronic F127 (18-23%) formulations combined high ability to solubilize βLAP (enhancement solubility factor up to 50), adequate gel temperature range (over 25 °C), and gel strength at 37 °C enough to guarantee the permanence of the formulation in the administration site for a period of time. βLAP release rate was finely tuned by the concentration of the polymer and the addition of RMβCD (diffusion coefficient ranging between 9 and 69 μg · cm(-2)). The ethanol increases βLAP release rate but simultaneously led to weak gels. This paper shows that βLAP formulations involving temperature-reversible Pluronic gels may be suitable for intratumoral drug delivery purposes.

Topics: Cyclodextrins; Delayed-Action Preparations; Diffusion; Ethanol; Gels; Humans; Materials Testing; Naphthoquinones; Neoplasms; Poloxalene; Polyethylenes; Polypropylenes; Temperature

The purpose of this analysis was to investigate the pharmacokinetics (PK) of sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of sepantronium.. Sepantronium was administered as a continuous intravenous infusion of 1.8-10.6 mg/m(2)/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose.. The PK of sepantronium was dose proportional in the dose range of 1.8-10.6 mg/m(2)/day. Age and sex did not significantly affect the PK of sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function.. While age and sex did not significantly affect the PK of sepantronium, moderate renal impairment increased exposure of sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Asian People; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Female; Humans; Imidazoles; Infusions, Intravenous; Inhibitor of Apoptosis Proteins; Japan; Male; Middle Aged; Naphthoquinones; Neoplasms; Renal Insufficiency; Retrospective Studies; Sex Factors; Survivin

We recently reported that shikonin and its analogs were a class of necroptotic inducers that could bypass cancer drug resistance. However, the molecular targets of shikonin are not known. Here, we showed that shikonin and its analogs are inhibitors of tumor-specific pyruvate kinase-M2 (PKM2), among which shikonin and its enantiomeric isomer alkannin were the most potent and showed promising selectivity, that is, shikonin and alkannin at concentrations that resulted in over 50% inhibition of PKM2 activity did not inhibit PKM1 and pyruvate kinase-L (PKL). Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. HeLa cells transfected with PKM1 showed reduced sensitivity to shikonin- or alkannin-induced cell death. To the best of our knowledge, shikonin and alkannin are the most potent and specific inhibitors to PKM2 reported so far. As PKM2 universally expresses in cancer cells and dictates the last rate-limiting step of glycolysis vital for cancer cell proliferation and survival, enantiomeric shikonin and alkannin may have potential in future clinical application.

Topics: Antineoplastic Agents; Cell Line, Tumor; Enzyme Inhibitors; Glucose; Glycolysis; Humans; Lactic Acid; Naphthoquinones; Neoplasms; Pyruvate Kinase

We recently discovered that 5, 8-O-dimethyl acylshikonin derivatives displayed the selectivity towards MCF-7 and no toxicity to normal cells. Herein, a series of the corresponding 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives were synthesized starting from shikonin. In vitro evidence of the cytotoxicities indicated that most of thecompounds were more active than or comparative to shikonin and retained the selectivity against MCF-7, MDA-MB-231 besides no toxicity in the normal cells. Also, in vivo anticancer activity of the positional isomers 5p, 6c further showed that 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives were more active than their corresponding 2-isomers. Thus, we may conclude that the position of the side chain of shikonin attached to 5,8-dimethoxy -1,4-naphthoquinone is associated with the antitumor activity.

Topics: Acylation; Animals; Antineoplastic Agents; Cell Survival; Drug Screening Assays, Antitumor; Female; Fibroblasts; Humans; Inhibitory Concentration 50; Isomerism; Male; Mice; Naphthoquinones; Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

Nor-β-lapachone has shown several biological properties. Regarding cytotoxic activity against cancer cell lines, it has been recognized as an important prototype. However, quinonoid drugs present a major challenge because of their toxicity. In this study, we evaluated the cytotoxicity and genetic toxicity of nor-β-lapachone in human lymphocytes and HL-60 leukemia cells and murine V79 fibroblasts, to shed some light on its selectivity toward cancer cells. As measured by MTT test, exposure of V79 cells to nor-β-lapachone resulted in a weak cytotoxicity (IC(50) = 13.41 μM), and at a concentration up to 21.9 μM, no cytotoxic effect was observed in lymphocytes, while in HL-60 cells, nor-β-lapachone elicited significantly greater cytotoxicity (IC(50) = 1.89 μM). Cultures coexposed to GSH-OEt showed an increased viability, which may indicate a neutralization of ROS generated by quinonoid treatment. In fact, only the highest concentrations of nor-β-lapachone (10 or 20 μM) caused an increase in oxidative stress in nontumor levels cells as measured by TBARS and nitrite/nitrate detection. This was accompanied by an alteration in intracellular thiol content. However, NAC pre-exposure restored the redox equilibrium of the cells and the concentration of thiol levels to control values. Nor-β-lapachone at 2.5 and 5 μM failed to induce DNA damage in nontumor cells, but at the highest concentrations tested, it induced single and double DNA strand breaks and increased the frequency of chromosomal aberrations. Interestingly, these damages were prevented by NAC pretreatment or exacerbated by prior exposure to the GSH-depleting agent 1-bromoheptane. In electrochemical experiments, nor-β-lapachone at the same concentrations as those used in genotoxic tests did not damage DNA directly, but at the highest concentration tested (200 μM), it caused a very weak DNA interaction. Corroborating electrochemical data, oxidative modifications of DNA bases were observed, as checked by DNA repair enzymes EndoIII and FPG, which reinforced the indirect actions caused by nor-β-lapachone through ROS generation and not via DNA intercalation. The DNA repair capacities were higher for nontumor cells than for leukemia cells, which may be related to the selective cytoxicity of nor-β-lapachone toward cancer cells. Our data suggest that ROS play an important role in nor-β-lapachone toxicity and that its DNA-damaging effect occurs only at concentrations several times higher than that needed for its anti

Topics: Animals; Antineoplastic Agents; Cell Survival; Cells, Cultured; Cricetinae; DNA; DNA Damage; Fibroblasts; HL-60 Cells; Humans; Lung; Lymphocytes; Mutagens; Naphthoquinones; Neoplasms; Oxidative Stress; Sulfhydryl Compounds

The synthesis and characterization of three novel iridium(III) complexes and one rhodium(III) complex with 1-nitroso-2-naphthol (3) chelating as a 1,2-naphthoquinone-1-oximato ligand are described. The reaction of mu(2)-halogenido-bridged dimers [(eta(5)-C(5)Me(5))IrX(2)](2) [X is Cl (1a), Br (1b), I (1c)] and [(eta(5)-C(5)Me(5))RhCl(2)](2) (2a) with 3 in CH(2)Cl(2) yields the mononuclear complexes (eta(5)-C(5)Me(5))IrX(eta(2)-C(10)H(6)N(2)O) (4a, 4b, 4c) and (eta(5)-C(5)Me(5))RhCl(eta(2)-C(10)H(6)N(2)O) (5a). All compounds were characterized by their (1)H and (13)C NMR, IR, and mass spectra, UV/vis spectra were recorded for 4a and 5a. The X-ray structure analyses revealed a pseudo-octahedral "piano-stool" configuration for the metals with bidentate coordination through oximato-N and naphthoquinone-O, forming a nearly planar five-membered metallacycle. The metal complexes 4a and 5a were evaluated in respect to their cytotoxicity and binding affinity toward double-stranded DNA. As determined in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, both exerted a much stronger cytotoxic effect toward HeLa and HL60 cancer cell lines than did cisplatin. The remarkable cytotoxicity of the compounds tested may be attributed to necrosis, rather than to apoptosis, as it is evidenced by the caspase-3/7 activation assay. No clear evidence was found for interaction with double-stranded DNA. The melting experiments showed no significant differences between thermodynamic parameters of intact DNA and DNA incubated with 3, 4a, or 5a, although these derivatives altered DNA recognition by the BamHI restriction enzyme. Therefore, the screened iridium and rhodium complexes 4a and 5a may still be interesting as potential anticancer drugs owing to their high cytotoxicity toward cancer cell lines, whereas they do not modify DNA in a way similar to that of cisplatin.

Topics: Antineoplastic Agents; Caspase 3; Caspase 7; Cell Death; Cell Line, Tumor; Cells, Cultured; Circular Dichroism; Coordination Complexes; Crystallography, X-Ray; DNA; HeLa Cells; Humans; Iridium; Models, Molecular; Naphthoquinones; Neoplasms; Rhodium

p53 is frequently mutated by genetic alternation or suppressed by various kinds of cellular signaling pathways in human cancers. Recently, we have revealed that p53 is suppressed and eliminated from cells by direct binding with oncogenic K-Ras-induced Snail. On the basis of the fact, we generated specific inhibitors against p53-Snail binding (GN25 and GN29). These chemicals can induce p53 expression and functions in K-Ras-mutated cells. However, it does not show cytotoxic effect on normal cells or K-Ras-wild-type cells. Moreover, GN25 can selectively activate wild-type p53 in p53(WT/MT) cancer cells. But single allelic mt p53 containing cell line, Panc-1, does not respond to our chemical. In vivo xenograft test also supports the antitumor effect of GN25 in K-Ras-mutated cell lines. These results suggest that our compounds are strong candidate for anticancer drug against K-Ras-initiated human cancers including pancreatic and lung cancers.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Child; Drug Evaluation, Preclinical; Female; Genes, ras; Humans; Mice; Mutation; Naphthoquinones; Neoplasms; Protein Binding; Small Molecule Libraries; Snail Family Transcription Factors; Transcription Factors; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes.

Topics: Antineoplastic Agents; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3B; Drug Evaluation, Preclinical; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; HCT116 Cells; HeLa Cells; HL-60 Cells; Humans; Inhibitory Concentration 50; Models, Biological; Naphthoquinones; Neoplasms; Substrate Specificity; Transcriptional Activation; Tumor Cells, Cultured

(23E)-25-Methylcycloart-23-en-3β-ol (1), a cycloartane-type triterpenoid featuring an unusual skeleton of 31 carbon atoms, (17E)-cycloart-17,26-dien-3β-ol (2), a new cycloartane-type triterpenoid, and the other two new compounds 4R-hydroxy-4-(9S-hydroxy-12-methylhexan-6-yl)-3-methylcyclopent-2-enone (6) and 7-hydroxy-5-(2'-hydroxy-4',5'-dimethoxyphenyl)-2-methoxy-6-methyl-1,4-naphthoquinone (7), together with three known cycloart-3β-ol triterpenoids (3-5) were isolated from aerial parts of Aphanamixis grandifolia. Their structures were elucidated by spectroscopic analysis, and that of 1 was confirmed by single-crystal X-ray diffraction. The absolute configuration of two carbon stereocenters of compound 6 was determined to be 4R,9S by means of circular dichroism (CD) and auxiliary chiral α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) derivatives, respectively. The compound 3 exhibited significant cytotoxicities against HL-60, Hep G2 and HeLa, and compounds 1, 2, 5, 6 and 7 exhibited modest cytotoxicities. No activity of compound 4 could be due to the absence of the hydroxyl group at C-24.

Topics: Antineoplastic Agents, Phytogenic; Cell Survival; Circular Dichroism; Crystallography, X-Ray; Cyclopentanes; Humans; Magnetic Resonance Spectroscopy; Meliaceae; Models, Molecular; Naphthoquinones; Neoplasms; Triterpenes

1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [(14)C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [(14)C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin's lymphoma (RL and Ramos) cell lines. The uptake of [(14)C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189-0.367 microM). The effects of various compounds on the uptake of [(14)C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [(14)C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC(50)) of several compounds for the uptake of [(14)C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.

Topics: Animals; Carbon Radioisotopes; Cell Line, Tumor; Drug Carriers; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lymphoma; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins; Naphthoquinones; Neoplasms; Survivin

Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica has been shown to exert anticancer and anti-proliferative activities in cells in culture as well as animal tumor models. In our previous paper, we have reported the cytotoxic action of plumbagin in plasmid pBR322 DNA as well as human peripheral blood lymphocytes through a redox mechanism involving copper. Copper has been shown to be capable of mediating the action of several plant-derived compounds through production of reactive oxygen species (ROS). The objective of the present study was to determine whether plumbagin induces apoptosis in human cancer cells through the same mechanism which we proposed earlier. Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, 3-(4,5-B-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell growth inhibition, histone/DNA ELISA, homogeneous caspase-3/7 assay for apoptosis as well as alkaline comet assay for DNA single-strand breaks detection in this report, we confirm that plumbagin causes effective cell growth inhibition, induces apoptosis and generates single-strand breaks in cancer cells. Incubation of cancer cells with scavengers of ROS and neocuproine inhibited the cytotoxic action of plumbagin proving that generation of ROS and Cu(I) are the critical mediators in plumbagin-induced cell growth inhibition. This study is the first to investigate the copper-mediated anticancer mechanism of plumbagin in human cancer cells and these properties of plumbagin could be further explored for the development of anticancer agents with higher therapeutic indices, especially for skin cancer.

Topics: Cell Death; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Shape; Comet Assay; Copper; Cytoprotection; Free Radical Scavengers; Humans; Naphthoquinones; Neoplasms; Oxidation-Reduction; Phenanthrolines; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Naphthoquinones; Neoplasm Proteins; Neoplasms; Signal Transduction; Survivin; Treatment Outcome

Ozonolysis of lapachol (1), resulting in an unusual formation of a potent antitumor agent 2-acetylfuranonaphthoquinone (3) along with the expected aldehyde 6, is described. The reaction of lapachol (1) with CAN in dry acetonitrile leading to biologically active furanonaphthoquinones is also reported. The antitumoral activity of the tested compounds on human DU-145 prostate carcinoma cells was evaluated following XTT assay. The results revealed that 2-(1-methylethenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (5), beta-lapachone (10) and dehydro-beta-lapachone diacetate (11) showed 100% inhibition at 25 microg/ml. All the tested samples showed dose-dependent activity.

Topics: Aldehydes; Antineoplastic Agents; Cell Line, Tumor; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Furans; Humans; Models, Chemical; Naphthoquinones; Neoplasms; Ozone; Plant Extracts; Quinones

Capecitabine is a chemotherapeutic drug for use in cancers. Hand-foot syndrome (HFS) is side effect of capecitabine which can lead the cessation of the therapy or dose reduction. Henna (Lawsonia inermis) is a traditionally used plant of Middle-East that is applied on hands and feet. Some of cancer patients in capecitabine treatment who developed HFS, we recommended to apply henna. In these patients, six patients were grade 3 HFS and four were grade 2 HFS. Complete response (CR) were seen in four of grade 3 HFS and all of grade 2; two grade 3 HFS improved to grade 1. So far, in the chemotherapy, there was no need of dose reduction and also no side effect of henna seen. Clinical improvement in these patients may relate to anti-inflammatory, antipyretic and analgesic effects of henna. Prospective studies are needed to show this therapeutic effect of henna.

Topics: Administration, Cutaneous; Adult; Aged; Antimetabolites, Antineoplastic; Capecitabine; Deoxycytidine; Female; Fluorouracil; Foot Dermatoses; Hand Dermatoses; Humans; Middle Aged; Naphthoquinones; Neoplasms; Paresthesia; Severity of Illness Index; Syndrome; Treatment Outcome

Beta,beta-dimethyl acryl shikonin is an extract from the root of plant Arnebia nobilis which has been shown to possess anti-cancer activity. However, its toxicity limited further development of shikonin as a therapeutic agent. Subsequently, several analogues of beta,beta-dimethyl acryl shikonin were synthesized. One of these analogues, shikonin 93/637 was found to be significantly less toxic compared to shikonin. This study is aimed to determine the cell cycle associated differences in the susceptibility of U937 cells to apoptosis induced by shikonin analogue 93/637 (SA). Lower concentrations of SA (approximately 100 nM) showed no significant changes in cell growth. However, higher concentrations (approximately 500 nM) resulted in growth inhibition of U937 cells after 48 h of treatment with SA as measured by MTT assay. Flow cytometric analysis showed that SA treatment resulted in blocking of cell cycle progression in G1 phase. Decreased expression of Cyclin D, CDK 4 and PCNA was observed with SA treatment corroborating the G1 block. DNA gel electrophoresis showed an oligonucleotide ladder pattern, a distinct characteristic of DNA fragmentation associated with programmed cell death. Ribonuclease protection assay revealed inhibition of bcl2 expression at transcriptional level. SA treatment also resulted in induction of caspase-3 activity. The results suggest the involvement of bcl2 and Caspase-3 in SA induced apoptosis of human U937 cells.

Topics: Apoptosis; Caspase 3; Cell Survival; Cinnamates; DNA Fragmentation; Enzyme Activation; Flow Cytometry; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Naphthoquinones; Neoplasms; Ribonucleases; Tetrazolium Salts; Thiazoles; Transcription, Genetic; U937 Cells

The synthesis and tumor-inhibitory activity of a series of aminonaphthoquinone derivatives of diospyrin, which was isolated from Diospyros montana Roxb., are presented here for the first time. An aminoacetate derivative showed the maximum (approximately 93%) increase in life span in vivo against murine Ehrlich ascites carcinoma (EAC) at a dose of 1 mg kg(-1)day(-1) (ip; five doses), and the lowest IC50 (0.06 microM) in vitro. Further, the same analogue also exhibited considerable enhancement in antiproliferative activity when evaluated against human cell lines, viz. malignant skin melanoma and epidermoid laryngeal carcinoma (IC50=0.06 and 0.92 microM, respectively) in comparison to the natural precursor, diospyrin (IC50=0.82 and 3.58 microM, respectively). Moreover, diospyrin and all its derivatives were found to show significantly greater (approximately 17- to 1441-fold) cytotoxicity against the tumor cells as compared to normal human lymphocytes. All these quinonoids generated substantial amounts of reactive oxygen species in EAC cells, more or less commensurate to their respective IC50 values.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cell Proliferation; Drug Design; Electrochemistry; Humans; Mice; Naphthoquinones; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species

Naphthalene is considered by the US Environmental Protection Agency to be a carcinogenic compound based on inhalation studies in rats. The primary metabolite of naphthalene is naphthalene 1,2-arene oxide. This unstable intermediate can lead to formation of 1-naphthol and naphthalene-1,2-dihydrodiol. Secondary metabolites include 1,2-dihydroxynaphthalene (1,2-DHN), which can be further oxidized to 1,2-naphthoquinone (1,2-NQ). Based on the metabolism of naphthalene and its similarity to the metabolic activation of carcinogenic natural estrogens, synthetic estrogens and benzene, we hypothesize that naphthalene is activated to initiate cancer by reaction of 1,2-NQ with DNA to form the depurinating adducts 1,2-DHN-4-N3Ade and 1,2-DHN-4-N7Gua. These adducts were synthesized by reaction of 1,2-NQ with Ade or dG in acetic acid/water/DMF (1:1:1). 1,2-NQ was reacted with DNA, and the depurinating 1,2-DHN-4-N3Ade and 1,2-DHN-4-N7Gua adducts were analyzed by ultraperformance liquid chromatography/tandem mass spectrometry and HPLC with electrochemical detection. After the reaction of 1,2-NQ with DNA, the N3Ade and N7Gua adducts were found. Similarly, when 1,2-DHN was activated by tyrosinase in the presence of DNA, higher amounts of the N3Ade and N7Gua adducts were detected. These same adducts were also formed when 1,2-DHN was activated by prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. These depurinating adducts are analogous to those obtained from the ortho-quinones of natural estrogens, synthetic estrogens and benzene. These results suggest that reaction of ortho-quinones with DNA by 1,4-Michael addition is a general mechanism of weak carcinogenesis that occurs with naphthalene and a number of other aromatic compounds.

Topics: Adenine; Carcinogens; DNA Adducts; Guanine; Kinetics; Molecular Structure; Naphthalenes; Naphthols; Naphthoquinones; Neoplasms

Here we described novel interactions of the mammalian selenoprotein thioredoxin reductase (TrxR) with nitroaromatic environmental pollutants and drugs. We found that TrxR could catalyze nitroreductase reactions with either one- or two-electron reduction, using its selenocysteine-containing active site and another redox active center, presumably the FAD. Tetryl and p-dinitrobenzene were the most efficient nitroaromatic substrates with a k(cat) of 1.8 and 2.8 s(-1), respectively, at pH 7.0 and 25 degrees C using 50 muM NADPH. As a nitroreductase, TrxR cycled between four- and two-electron-reduced states. The one-electron reactions led to superoxide formation as detected by cytochrome c reduction and, interestingly, reductive N-denitration of tetryl or 2,4-dinitrophenyl-N-methylnitramine, resulting in the release of nitrite. Most nitroaromatics were uncompetitive and noncompetitive inhibitors with regard to NADPH and the disulfide substrate 5,5'-dithiobis(2-nitrobenzoic acid), respectively. Tetryl and 4,6-dinitrobenzofuroxan were, however, competitive inhibitors with respect to 5,5'-dithiobis(2-nitrobenzoic acid) and were clearly substrates for the selenolthiol motif of the enzyme. Furthermore, tetryl and 4,6-dinitrobenzofuroxan efficiently inactivated TrxR, likely by alkylation of the selenolthiol motif as in the inhibition of TrxR by 1-chloro-2,4-dinitrobenzene/dinitrochlorobenzene (DNCB) or juglone. The latter compounds were the most efficient inhibitors of TrxR activity in a cellular context. DNCB, juglone, and tetryl were highly cytotoxic and induced caspase-3/7 activation in HeLa cells. Furthermore, DNCB and juglone were potent inducers of apoptosis also in Bcl2 overexpressing HeLa cells or in A549 cells. Based on these findings, we suggested that targeting of intracellular TrxR by alkylating nitroaromatic or quinone compounds may contribute to the induction of apoptosis in exposed human cancer cells.

Topics: Animals; Apoptosis; Binding Sites; Caspase 3; Caspase 7; Caspases; Cell Line, Tumor; Dinitrobenzenes; Dithionitrobenzoic Acid; Enzyme Activation; Enzyme Inhibitors; Humans; Molecular Structure; Naphthoquinones; Neoplasms; Nitrogen Compounds; Oxidation-Reduction; Proto-Oncogene Proteins c-bcl-2; Sulfhydryl Reagents; Superoxides; Thioredoxin-Disulfide Reductase

1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate (SH-7), a new naphthoquinone compound, derived from shikonin, exhibited obvious inhibitory actions on topoisomerase II (Topo II) and topoisomerase I (Topo I), which were stronger than its mother compound shikonin. Notably, the SH-7's inhibitory potency on Topo II was much stronger than that on Topo I. In addition, SH-7 significantly stabilized Topo II-DNA cleavable complex and elevated the expression of phosphorylated-H2AX. The in vitro cell-based investigation demonstrated that SH-7 displayed wide cytotoxicity in diversified cancer cell lines with the mean IC(50) value of 7.75 microM. One important finding is SH-7 displayed significant cytotoxicity in the 3 MDR cell lines, with an average IC(50) value nearly equivalent to that of the corresponding parental cell lines. The average resistance factor (RF) of SH-7 was 1.74, which was much lower than those of reference drugs VP-16 (RF 145.92), ADR (RF 105.97) and VCR (RF 197.39). Further studies illustrated that SH-7 had the marked apoptosis-inducing function on leukemia HL-60 cells, which was validated to be of mitochondria-dependence. The in vivo experiments showed that SH-7 had inhibitory effects on S-180 sarcoma implanted to mice, SMMC-7721, BEL-7402 human hepatocellular carcinoma and PC-3 human prostate cancer implanted to nude mice. Taken together, these results suggest that SH-7 induces DSBs as a Topo II inhibitor, which was crucial to activate the apoptotic process, and subsequently accounts for its both in vitro and in vivo antitumor activities. The well-defined Topo II inhibitory activity, antitumor effects particularly with its obvious anti-MDR action, better solubility and less toxicity make SH-7 as a potential antitumor drug candidate for further research and development.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Electrophoresis, Agar Gel; Female; Flow Cytometry; Humans; Leukemia; Liver Neoplasms; Male; Mice; Mice, Nude; Naphthoquinones; Neoplasms; Prostatic Neoplasms; Sarcoma; Topoisomerase II Inhibitors; Transplantation, Heterologous

Most efforts thus far have been devoted to develop apoptosis inducers for cancer treatment. However, apoptotic pathway deficiencies are a hallmark of cancer cells. We propose that one way to bypass defective apoptotic pathways in cancer cells is to induce necrotic cell death. Here we show that selective induction of necrotic cell death can be achieved by activation of the DNA damage response pathways. While beta-lapachone induces apoptosis through E2F1 checkpoint pathways, necrotic cell death can be selectively induced by beta-lapachone in a variety of cancer cells. We found that beta-lapachone, unlike DNA damaging chemotherapeutic agents, transiently activates PARP1, a main regulator of the DNA damage response pathway, both in vitro and in vivo. This occurs within minutes of exposure to beta-lapachone, resulting in selective necrotic cell death. Inhibition of PAR blocked beta-lapachone-induced necrosis. Furthermore, necrotic cell death induced by beta-lapachone was significantly reduced in PARP1 knockout cell lines. Our data suggest that selective necrotic cell death can be induced through activation of DNA damage response pathways, supporting the idea of selective necrotic cell death as a therapeutic strategy to eliminate cancer cells.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; DNA Damage; Female; HeLa Cells; Humans; Mice; Mice, Knockout; Naphthoquinones; Necrosis; Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Signal Transduction; Xenograft Model Antitumor Assays

Metastasis is the major process responsible for the death in cancer patients. In the search for more effective antineoplasic drugs, many substances are under investigation, among them lapachol. This study aims to examine the molecular and morphological alterations caused by lapachol treatment, as well as its effects on the intrinsic tissue invasive property of this cell line. HeLa cells were exposed to different concentrations of lapachol, and the resulting alterations on cellular protein profile, morphology and invasiveness property were studied. At 400 microg/ml, cellular viability remains unchanged, but lapachol induces alterations in the protein profile and inhibits the invasiveness of HeLa cells in CAM model. With these results, we can conclude that lapachol has a great potential of application in fighting metastasis.

Topics: Antineoplastic Agents, Phytogenic; HeLa Cells; Humans; Naphthoquinones; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms

beta-Lapachone, an o-naphthoquinone, induces a novel caspase- and p53-independent apoptotic pathway dependent on NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 reduces beta-lapachone to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound, perpetuating a futile redox cycle. A deficiency or inhibition of NQO1 rendered cells resistant to beta-lapachone. Thus, beta-lapachone has great potential for the treatment of specific cancers with elevated NQO1 levels (e.g., breast, non-small cell lung, pancreatic, colon, and prostate cancers). We report the development of mono(arylimino) derivatives of beta-lapachone as potential prodrugs. These derivatives are relatively nontoxic and not substrates for NQO1 when initially diluted in water. In solution, however, they undergo hydrolytic conversion to beta-lapachone at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. NQO1 enzyme assays, UV-visible spectrophotometry, high-performance liquid chromatography-electrospray ionization-mass spectrometry, and nuclear magnetic resonance analyses confirmed and monitored conversion of each derivative to beta-lapachone. Once converted, beta-lapachone derivatives caused NQO1-dependent, mu-calpain-mediated cell death in human cancer cells identical to that caused by beta-lapachone. Interestingly, coadministration of N-acetyl-l-cysteine, prevented derivative-induced cytotoxicity but did not affect beta-lapachone lethality. Nuclear magnetic resonance analyses indicated that prevention of beta-lapachone derivative cytotoxicity was the result of direct modification of these derivatives by N-acetyl-l-cysteine, preventing their conversion to beta-lapachone. The use of beta-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation.

Topics: Cell Division; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Humans; Magnetic Resonance Spectroscopy; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Prodrugs; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Structure-Activity Relationship

A 96-well fluorescence-based assay has been developed for the rapid screening of potential cytotoxic and bacteriocidal compounds. The assay is based on detection of green fluorescent protein (GFP) in HeLa human carcinoma cells as well as gram negative (Escherichia coli) and gram positive bacteria (Mycobacterium avium). Addition of a toxic compound to the GFP marked cells resulted in the loss of the GFP fluorescence which was readily detected by fluorometry. Thirty-nine distinct naphthoquinone derivatives were screened and several of these compounds were found to be toxic to all cell types. Apart from differences in overall toxicity, two general types of toxic compounds were detected, those that exhibited toxicity to two or all three of the cell types and those that were primarily toxic to the HeLa cells. Our results demonstrate that the parallel screening of both eukaryotic and prokaryotic cells is not only feasible and reproducible but also cost effective.

Topics: Antineoplastic Agents; Bacteria; Biological Assay; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Escherichia coli; Fluorometry; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; HeLa Cells; Humans; Indicators and Reagents; Microscopy, Fluorescence; Models, Chemical; Mycobacterium avium; Naphthoquinones; Neoplasms

The purpose of the present study was to evaluate the efficacy of mild hyperthermia to potentiate the anticancer effects of beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione) by up-regulating NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells.. Effects of beta-lapachone alone or in combination with mild heating on the clonogenic survival of FSaII fibrosarcoma cells of C3H mice and A549 human lung tumor cells in vitro was determined. Effects of heating on the NQO1 level in the cancer cells in vitro were assessed using Western blot analysis for NQO1 expression, biochemical determination of NQO1 activity, and immunofluorescence microscopy for NQO1 expression. Growth of FSaII tumors in the hind legs of C3H mice was determined after treating the host mice with i.p. injection of 45 mg/kg beta-lapachone followed by heating the tumors at 42 degrees C for 1 hour every other day for four times.. Incubation of FSaII tumor cells and A549 tumor cells with beta-lapachone at 37 degrees C reduced clonogenic survival of the cells in dose-dependent and incubation time-dependent manner. NQO1 level in the cancer cells in vitro increased within 1 hour after heating at 42 degrees C for 1 hour and remained elevated for >72 hours. The clonogenic cell death caused by beta-lapachone increased in parallel with the increase in NQO1 levels in heated cells. Heating FSaII tumors in the legs of C3H mice enhanced the effect of i.p.-injected beta-lapachone in suppressing tumor growth.. We observed for the first time that mild heat shock up-regulates NQO1 in tumor cells. The heat-induced up-regulation of NQO1 enhanced the anticancer effects of beta-lapachone in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Combined Modality Therapy; Dicumarol; Enzyme Inhibitors; Humans; Hyperthermia, Induced; Mice; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Up-Regulation

Most chemotherapeutic drugs kill cancer cells by indirectly activating checkpoint-mediated apoptosis after creating nonselective damage to DNA or microtubules, which accounts for their toxicity toward normal cells. We seek to target cancer cells by directly activating checkpoint regulators without creating such damage. Here, we show that beta-lapachone selectively induces apoptosis in cancer cells without causing the death of nontransformed cells in culture. This unusual selectivity against cancer cells is preceded by activation of S-phase checkpoint and selective induction of E2F1, a regulator of checkpoint-mediated apoptosis. This study suggests direct checkpoint activation as a strategy against cancer.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Cycle Proteins; Cell Death; Cell Division; Cell Line; Cell Transformation, Neoplastic; Coloring Agents; DNA-Binding Proteins; Dose-Response Relationship, Drug; E2F Transcription Factors; E2F1 Transcription Factor; Flow Cytometry; Humans; Models, Biological; Naphthoquinones; Neoplasms; Retinoblastoma Protein; S Phase; Tetrazolium Salts; Thiazoles; Transcription Factors; Tumor Cells, Cultured

We investigated the release of iron from ferritin in aqueous solutions exposed to high-frequency ultrasound (US). Our data suggests that superoxide produced as a result of ultrasonic cavitation acts as a reducing agent, enabling the release of iron from ferritin. We also found that the release of ferritin iron during US exposure is enhanced by the addition of 5-hydroxy-1,4-naphthoquinone. We hypothesize that this quinone is ultrasonically transformed into a semiquinone radical capable of directly and indirectly reducing Fe(3+) in ferritin to soluble Fe(2+). Our proposed mechanism for the release of iron from ferritin adds new insight to the synergistic effect of quinone-containing cancer drugs with US.

Topics: Antineoplastic Agents; Combined Modality Therapy; Ferritins; Iron; Naphthoquinones; Neoplasms; Oxidation-Reduction; Superoxides; Ultrasonic Therapy; Ultrasonics

Diospyrin, a bisnaphthoquinonoid natural product, and three synthetic derivatives have been tested for their action in four human cancer cell lines: acute myeloblastic leukemia (HL-60), chronic myelogenic leukemia (K-562), breast adenocarcinoma (MCF-7) and cervical epithelial carcinoma (HeLa). In cells grown in appropriate media several derivatives elicited cytotoxicity as assessed by Trypan Blue dye exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide reduction and DNA synthesis. Diethyl ether derivative (D7) was most effective in this regard while the parent compound diospyrin (D1) was least active (D7>D3>D2>D1). D7 was not cytotoxic toward normal human lymphocytes, suggesting its action is specific for tumor cells. On microscopic examination D7-treated cells exhibited characteristic morphological features of apoptosis, such as cell shrinkage and formation of apoptotic bodies. Fluorescent staining with propidium iodide revealed distinct chromatin condensation and nuclear fragmentation. The apoptotic index paralleled cytotoxic parameters, and fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a typical ladder pattern. D7-induced apoptosis was mediated via activation of caspase 3 and caspase 8.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Division; Diospyros; Humans; Microscopy, Fluorescence; Naphthoquinones; Neoplasms; Plant Bark; Tumor Cells, Cultured

The 50% growth inhibition toxicity (IC50 at 72 h) of 16 synthetic and 2 phytochemical natural analogs of furanonaphthoquinones (naphtho[2,3-b]furan-4,9-dione; FNQ) and 2 analogs of isofuranonaphthoquinones was assayed in vitro in respect to established human cervical cancer and lung adenocarcinoma cells in comparison with human uterine endocervical, tracheal and bronchiolar epithelial cells and fibroblasts. Prostate, cholangio, colon, laryngeal, and tongue carcinoma cell lines and two osteosarcoma cell lines were also used for the assay. The IC50 ratio of normal cells to cancer cells was estimated in order to represent preferential antitumor activity. Two analogs, 2-methylnaphtho[2,3-b]furan-4, 9-dione (FNQ3) and 2-methyl-5(or 8)-hydroxynaphtho[2,3-b]furan-4, 9-dione (FNQ13) showed 10.4 to 14.1 IC50 ratios for all carcinoma cells used, indicating a wide spectrum. Among different carcinomas, there was no difference or variety in the IC50 ratio of a single analog. A moderate IC50 ratio (3.1-4.7) was also found in nine analogs, but seven others were equally cytotoxic (less than 2.6) to both cancer and normal cells. Two isofuranonaphthoquinone derivatives were ineffective, but a thieno derivative was equally cytotoxic to all cells tested. On the basis of the IC50 ratio data and the structure of the furanonaphthoquinones, the following structural activity (selectivity) relationship can be postulated: (i) the presence of an alkyl group at position 2 enhances the IC50 ratio, particularly the methyl group; (ii) a hydroxyl group at position 5 or 8 enhances the IC50 ratio; and (iii) methylation of the phenolic hydroxyl group leads to a decrease of potency. These results indicate that FNQ3, 13, and some other analogs are more preferentially cytotoxic to human tumor cells than to normal cells, unlike mitomycin-C, adriamycin, carboplatin, and methotrexate which are cytotoxic to the both. In nude mouse xenograft tests, FNQ3 demonstrated a significant antitumor activity with T/C% values of 16. 6 to 41.6 against several human carcinoma and osteosarcoma cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Screening Assays, Antitumor; Epithelial Cells; Fibroblasts; HeLa Cells; Humans; Male; Mice; Mice, Inbred BALB C; Naphthoquinones; Neoplasm Transplantation; Neoplasms; Tumor Cells, Cultured

This present work was carried out in order to study the effect of Lapachol (LAP) administrated to rats simultaneously with a chemical carcinogen 20-Methylcholanthrene (MCA). Animals were divided in 4 groups: A-Group treated with 80 mg of MCA I(n = 11 rats), B-Group treated with 80 mg of MCA+LAP 100 mg/kg weight/day, (n = 15 rats), C-Group treated with LAP 100 mg/kg weight/day (n = 12 rats), D-Group control-no treatment (n = 13 rats). Cytological studies as well as cytochemical techniques allowed the recognition of benign and malignant conditions at the time of the tumor appearance. Histopathological evaluation posteriorly confirmed the development of tumors in 53% of the animals in group B. Morphologically consistent with poorly differentiated adenocarcinomas of the salivary glands and fibroadenomas of the breast in 18.2% (2/11) of the rats in group A. Besides the presence of one or several supra-hepatic nodules in vecinity of the suspensory ligament corresponding to nodular hyperplasia were observed in 33% (4/12) of group C and in 13.3% (12/15) of group B. No nodules were observed in groups A and D. Tubular dilatation of kidneys were noted in 60% (9/15) and 83.3/ (10/12) of the rats in group E and C respectively. From the original salivary gland tumor a series of transplantables tumors were developed and followed by cytological evaluations. The importance of the cytological and histopathological diagnosis for the pharmacological effects studies of certain drugs like Lapachol that are widely used as antitumoral agents without exact knowledge of the adverse effects is emphasized.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinogens; Methylcholanthrene; Naphthoquinones; Neoplasms; Rats; Rats, Sprague-Dawley

Dichloroallyl lawsone (DCL, NSC-126771), a synthetic analogue of the antimalarial lapachol, is potentially useful in cancer chemotherapy. Unlike most anticancer agents, DCL is not significantly myelosuppressive in animals but it induces acute cardiac toxicity in the rhesus monkey. This cardiac toxicity seems to be correlated with the maximal plasma DCL concentration, about 130 mg/L in the monkey. We have studied DCL pharmacokinetics in patients in an attempt to define safe dose limits for the Phase I clinical trial. After the rapid intravenous infusion of 10 mg/m2 of radioactive [1- or 4-14C]DCL, 250 muCi per patient, the mean peak plasma concentration of unchanged DCL in four patients was 2.9 +/- 0.3 mg/L. The drug had a mean initial plasma half-life of 48.9 +/- 19 min and a terminal half-life of 20.3 +/- 1.8 hr, with a C X t of 50.1 +/- 12 mg/L/hr, and a clearance rate of 0.08 ml/kg/min. These data suggest that in clinical trials the DCL dose given by rapid intravenous infusion should not exceed 450 mg/m2 so that the maximal plasma drug concentration remains below 130 mg/L.

Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Half-Life; Humans; Infusions, Parenteral; Kinetics; Leukemia; Naphthoquinones; Neoplasms

Topics: Cell Transformation, Neoplastic; Cybernetics; Diethylstilbestrol; Hot Temperature; Hydrogen Peroxide; Hydrogen-Ion Concentration; Membranes; Naphthoquinones; Neoplasms; Vitamin K

Topics: Animals; Female; Humans; Male; Naphthoquinones; Neoplasms; Rabbits; Tritium

Topics: Chromatography, Paper; Humans; Naphthoquinones; Neoplasms; Tritium

Topics: Animals; Chlorprothixene; Fluorouracil; Hydrocarbons; Mammary Neoplasms, Animal; Mice; Naphthoquinones; Neoplasms; Neoplasms, Experimental; Thiazoles

Topics: Antineoplastic Agents; Autoradiography; Humans; Naphthoquinones; Neoplasms; Radiopharmaceuticals; Retinoids; Tritium; Vitamin K

Topics: Animals; Antifibrinolytic Agents; Characidae; Leukemia; Leukemia, Lymphoid; Naphthoquinones; Neoplasms; Neoplasms, Experimental; Sodium; Tritium; Vitamin K

Topics: Animals; Antineoplastic Agents; Ascites; Mice; Naphthoquinones; Neoplasms

Topics: Antifibrinolytic Agents; Humans; Naphthoquinones; Neoplasms; Retinoids; Vitamin K

Topics: Animals; Carbohydrate Metabolism; Carbohydrates; Glycolysis; Naphthoquinones; Neoplasms; Neoplasms, Experimental

Topics: Antineoplastic Agents; Humans; Naphthoquinones; Neoplasms

Topics: Animals; Characidae; Diphosphates; Naphthoquinones; Neoplasms; Radiation-Sensitizing Agents; Radiotherapy; Sodium; Vitamin K

Topics: Animals; Characidae; Diphosphates; Humans; Ions; Naphthoquinones; Neoplasms; Sodium; Tetracycline