phenanthrenes and Neoplasms

Celastrol, triptolide and triptonide are the most significant active ingredients of Tripterygium wilfordii Hook F (TWHF). In 2007, the 'Cell' journal ranked celastrol, triptolide, artemisinin, capsaicin and curcumin as the five natural drugs that can be developed into modern medicinal compounds. In this review, we collected relevant data from the Web of Science, PubMed and China Knowledge Resource Integrated databases. Some information was also acquired from government reports and conference papers. Celastrol, triptolide and triptonide have potent pharmacological activity and evident anti-cancer, anti-tumor, anti-obesity and anti-diabetes effects. Because these compounds have demonstrated unique therapeutic potential for acute and chronic inflammation, brain injury, vascular diseases, immune diseases, renal system diseases, bone diseases and cardiac diseases, they can be used as effective drugs in clinical practice in the future. However, celastrol, triptolide and triptonide have certain toxic effects on the liver, kidney, cholangiocyte heart, ear and reproductive system. These shortcomings limit their clinical application. Suitable combination therapy, new dosage forms and new routes of administration can effectively reduce toxicity and increase the effect. In recent years, the development of different targeted drug delivery formulations and administration routes of celastrol and triptolide to overcome their toxic effects and maximise their efficacy has become a major focus of research. However, in-depth investigation is required to elucidate the mechanisms of action of celastrol, triptolide and triptonide, and more clinical trials are required to assess the safety and clinical value of these compounds.

Topics: Diterpenes; Epoxy Compounds; Humans; Neoplasms; Phenanthrenes; Triterpenes

Cancer is a silent killer and remains to pose major health problems globally. Amongst the several biological targets, DNA is one of the most striking targets in cancer chemotherapy. Owing to its planar structure, phenanthrene and its derivatives exhibit potential cytotoxicity by intercalating between the DNA base pairs and by inhibiting the enzymes that are involved in the synthesis of DNA. However, due to the off-target effects and resistance, the development of novel chemotherapeutic agents would be meritorious. In this regard, we present a detailed review on the development of phenanthrene-based derivatives reported in the last quinquennial. This review mainly focuses on the synthetic aspects and strategies to procure the fused phenanthrene derivatives such as (i) phenanthroindolizidines, phenanthroquinolizidine, phenanthroimidazoles, podophyllotoxin-based phenanthrenes, and dihydrophenanthrodioxine derivatives, (ii) phenanthrene conjugates with other pharmacologically significant pharmacophores, and (iii) phenanthrene-metal complexes. This review also edifies their potential in vitro cytotoxicity evaluation against various carcinoma cell lines in submicromolar to nanomolar ranges. Additionally, computational studies and structure-activity relationships (SARs) have also been presented to highlight the essential features of the designed congeners. Thus, this review would aid in the development of novel derivatives in future as potential cytotoxic agents in the field of medicinal chemistry.

Topics: Antineoplastic Agents; DNA; Humans; Molecular Structure; Neoplasms; Phenanthrenes; Structure-Activity Relationship

Covering: 2000 to 2020 Triptolide is a bioactive diterpene triepoxide isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal plant whose extracts have been used as anti-inflammatory and immunosuppressive remedies for centuries. Although triptolide and its analogs exhibit potent bioactivities against various cancers, and inflammatory and autoimmune diseases, none of them has been approved to be used in the clinic. This review highlights advances in material sourcing, molecular mechanisms, clinical progress and new drug design strategies for triptolide over the past two decades, along with some prospects for the future course of development of triptolide.

Topics: Animals; Autoimmune Diseases; Diterpenes; Drug Design; Drug Discovery; Epoxy Compounds; Forecasting; Humans; Inflammation; Neoplasms; Phenanthrenes; Tripterygium

In respect to the enhanced incidence rate of cancer worldwide, studies have focused on cancer therapy using novel strategies. Chemotherapy is a common strategy in cancer therapy, but its adverse effects and chemoresistance have limited its efficacy. So, attempts have been directed towards minimally invasive cancer therapy using plant derived-natural compounds. Cryptotanshinone (CT) is a component of salvia miltiorrihiza Bunge, well-known as Danshen and has a variety of therapeutic and biological activities such as antioxidant, anti-inflammatory, anti-diabetic and neuroprotective. Recently, studies have focused on anti-tumor activity of CT against different cancers. Notably, this herbal compound is efficient in cancer therapy by targeting various molecular signaling pathways. In the present review, we mechanistically describe the anti-tumor activity of CT with an emphasis on molecular signaling pathways. Then, we evaluate the potential of CT in cancer immunotherapy and enhancing the efficacy of chemotherapy by sensitizing cancer cells into anti-tumor activity of chemotherapeutic agents, and elevating accumulation of anti-tumor drugs in cancer cells. Finally, we mention strategies to enhance the anti-tumor activity of CT, for instance, using nanoparticles to provide targeted drug delivery.

Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Phenanthrenes

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.

Topics: Animals; Antigens, CD; Antineoplastic Agents; B7 Antigens; B7-H1 Antigen; Camptothecin; CTLA-4 Antigen; Diterpenes; Epoxy Compounds; Flavonoids; Hepatitis A Virus Cellular Receptor 2; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Isothiocyanates; Lymphocyte Activation Gene 3 Protein; Mice; Neoplasms; Phenanthrenes; Phytochemicals; Plant Extracts; Programmed Cell Death 1 Receptor; Receptors, Immunologic; Saponins; Sulfoxides; Terpenes; Tumor Microenvironment

Triptolide (TPL), the active component of Tripterygium wilfordii Hook F (Twhf) has been used to treat cancer and bone loss conditions for over two hundred years in traditional Chinese medicine (TCM). In this paper, we reviewed the specific molecular mechanisms in the treatment of cancer, bone loss and cardiovascular disease. In addition, we analyze the toxicity of TPL and collect some optimized derivatives extracted from TPL. Although positive results were obtained in most cell culture and animal studies, further studies are needed to substantiate the beneficial effects of TPL.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Arthritis, Rheumatoid; Autophagy; Cardiovascular Diseases; Diterpenes; Epoxy Compounds; Humans; Medicine, Chinese Traditional; Neoplasms; Osteoporosis; Phenanthrenes; Plant Extracts; Signal Transduction; Tripterygium

Tumors are major chronic diseases and seriously threaten human health all over the world. How to effectively control and cure tumors is one of the most pivotal problems in the medical field. At present,surgery,radiotherapy and chemotherapy are still the main treatment methods. However,the side effects of radiotherapy and chemotherapy cannot be underestimated. Therefore,it is of great practical significance to find new anti-cancer drugs with low toxicity,high efficiency and targeting to cancer cells. With the increasing incidence of tumor,the anti-tumor effect of traditional Chinese medicine has increasingly become a research hotspot. Triptolide,which is a natural diterpenoid active ingredient derived from of Tripterygium wilfordii,as one of the highly active components,has anti-inflammatory,immunosuppressive,anti-tumor and other multiple effects. A large number of studies have confirmed that it has good anti-tumor activity against various tumors in vivo and in vitro. It can play an anti-tumor role by inhibiting the proliferation of cancer cells,inducing apoptosis of cancer cells,inducing autophagy of cancer cells,blocking the cell cycle,inhibiting the migration,invasion and metastasis of cancer cells,reversing multidrug resistance,mediating tumor immunity and inhibiting angiogenesis. On the basis of literatures,this paper reviews the anti-tumor effect and mechanism of triptolide,and analyzes the current situation of triptolide combined with other chemotherapy drugs,in order to promote deep research and better clinical application about triptolide.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cell Cycle Checkpoints; Diterpenes; Epoxy Compounds; Humans; Neoplasms; Phenanthrenes; Tripterygium

As a major active component extracted from traditional Chinese herb Tripterygium wilfordii Hook F, triptolide exhibits multiple pharmacological effects. Autophagy is an evolutionary conserved intracellular catabolic process involved in cytoplasmic materials degradation. Autophagic dysfunction contributes to the pathologies of many human diseases, which makes it a promising therapeutic target. Recent studies have shown that triptolide exerts neuroprotection, anti-tumor activities, organ toxicity, and podocyte protection by modulating autophagy. This article highlights the current information on triptolide-modulated autophagy, analyzes the possible pathways involved, and describes the crosstalk between autophagy and apoptosis modulated by triptolide, in hope of providing implications for the roles of autophagy in pharmacological effects of triptolide and expanding its novel usage as an autophagy modulator.

Topics: Animals; Apoptosis; Autophagy; Diterpenes; Epoxy Compounds; Humans; Neoplasms; Neuroprotective Agents; Phenanthrenes; Podocytes

In recent years, cancer has become the most common human disease worldwide, and great attentions have been paid to clarifying the carcinogenesis and identifying new effective antitumor therapy. Although great progress has been made in this research field, human malignant diseases could still not be radically cured. Thunder god vine is a herbal medicine, which has proved to exert efficient antitumor activity in various human cancers such as lung cancer, pancreatic cancer, and colon cancer. In vivo and in vitro experiments showed that thunder god vine extract triptolide could inhibit tumor cell proliferation, cell migration, and cell invasion. Here, we overviewed the functional role of triptolide in human malignancies and its promising therapeutic potential in treating such deadly diseases.

Topics: Antineoplastic Agents, Alkylating; Diterpenes; Epoxy Compounds; Humans; Neoplasms; Phenanthrenes; Prognosis

The kinesin motor KIFC1 has been suggested as a potential chemotherapy target due to its critical role in clustering of the multiple centrosomes found in cancer cells. In this regard, KIFC1 seems to be non-essential in normal somatic cells which usually possess only two centrosomes. Moreover, KIFC1 is also found to initiatively drive tumor malignancy and metastasis by stabilizing a certain degree of genetic instability, delaying cell cycle and protecting cancer cell surviving signals. However, that KIFC1 also plays roles in other specific cell types complicates the question of whether it is a promising chemotherapy target for cancer treatment. For example, KIFC1 is found functionally significant in vesicular and organelle trafficking, spermiogenesis, oocyte development, embryo gestation and double-strand DNA transportation. In this review we summarize a recent collection of information so as to provide a generalized picture of ideas and mechanisms against and in favor of KIFC1 as a chemotherapy target. And we also drew the conclusion that KIFC1 is a promising chemotherapy target for some types of cancers, because the side-effects of inhibiting KIFC1 mentioned in this review are theoretically easy to avoid, while KIFC1 is functionally indispensable during mitosis and malignancy of multi-centrosome cancer cells. Further investigations of how KIFC1 is regulated throughout the mitosis in cancer cells are needed for the understanding of the pathways where KIFC1 is involved and for further exploitation of indirect KIFC1 inhibitors.

Topics: Alanine; Antineoplastic Agents; Centrosome; DNA; Female; Humans; Kinesins; Mitosis; Molecular Targeted Therapy; Neoplasms; Oocytes; ortho-Aminobenzoates; Phenanthrenes; Phenylalanine; Pregnancy; Protein Transport; Pyridines; Signal Transduction; Spermatogenesis

To discover and develop novel natural compounds, active ingredients, single herbs and combination formulas or prescriptions in traditional Chinese medicine (TCM) with therapeutic selectivity that can preferentially kill cancer cells and inhibit the amplification of cancer without significant toxicity is an important area in cancer therapy. A lot of valuable TCMs were applied as alternative or complementary medicines in the United States and Europe. But these TCMs, as one of the main natural resources, were widely used to research and develop new drugs in Asia. In TCMs, some specific herbs, animals, minerals and combination formulas were recorded and exploited due to their active ingredients and specific natural compounds with antitumor activities. The article focused on the antitumor properties of natural compounds and combination formulas or prescriptions in TCMs, described its influence on tumor progression, angiogenesis, metastasis, and revealed its mechanisms of antitumor and inhibitory action. Among the nature compounds, triptolide, berberine, matrine, oxymatrine, kurarinone and deoxypodophyllotoxin (DPT) with specific molecular structures have been separated, purified, and evaluated their antitumor properties in vitro and in vivo. Cancer is a multifactorial and multistep disease, so the treatment effect of combination formulas and prescriptions in TCMs involving multi-targets and multi-signal pathways on tumor may be superior than that of agents targeting a single molecular target alone. Shi Quan Da Bu Tang and Yanshu injection, as well known combination formulas and prescriptions in TCMs, have shown an excellent therapeutic effect on cancer.

Topics: Alkaloids; Amphibian Venoms; Animals; Antineoplastic Agents, Phytogenic; Berberine; Diterpenes; Drug Combinations; Drug Discovery; Drugs, Chinese Herbal; Epoxy Compounds; Flavonoids; Humans; Matrines; Medicine, Chinese Traditional; Molecular Conformation; Molecular Targeted Therapy; Neoplasms; Phenanthrenes; Plants, Medicinal; Podophyllotoxin; Quinolizines

The plant family Amaryllidaceae is of provenance in the South African region which is known to harbor about a third of the global complement of around 1000 species. It has widespread usage in the traditional medicinal practices of the indigenous peoples of the region. As a consequence and given its unique alkaloid principles, its members have provided a viable platform for phytochemical based drug discovery. The medicinal potential of the family has been realized through the commercialization of galanthamine as an Alzheimer's drug due to its potent and selective inhibitory activity against the enzyme acetylcholinesterase. Further promising chemotherapeutic candidates of the family reside with the phenanthridone class of alkaloids such as pancratistatin which exhibit potent and cell line specific antiproliferative properties with significant potential for clinical development. Despite these interesting medicinal attributes, plants of the Amaryllidaceae are known to be poisonous and several of them have been classified as such. This survey taking into consideration Amaryllidaceae plants native to South Africa aims to strike a balance between the medicinal potential of the family on one hand and its adverse and toxic effects on the other.

Topics: Alkaloids; Amaryllidaceae Alkaloids; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antifungal Agents; Antiparasitic Agents; Ethnopharmacology; Hallucinogens; Humans; Isoquinolines; Liliaceae; Medicine, African Traditional; Mental Disorders; Neoplasms; Phenanthrenes; Plants, Medicinal; Plants, Toxic; South Africa

Cryptotanshinone is one of the major tanshinones isolated from the roots of the plant Salvia miltiorrhiza Bunge (Danshen). Danshen has been widely used in traditional Chinese medicine for treatment of a variety of diseases, including coronary artery disease, acute ischemic stroke, hyperlipidemia, chronic renal failure, chronic hepatitis, and Alzheimer's disease, showing no serious adverse effects. Recent studies have shown that cryptotanshinone not only possesses the potential for treatment and prevention of the above-mentioned diseases, but also is a potent anticancer agent. Here we briefly summarize the physical and chemical properties and the pharmacokinetic profiles of cryptotanshinone, and then comprehensively review its anticancer activities as well as the underlying mechanisms.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Proliferation; Drugs, Chinese Herbal; Humans; Neoplasms; Phenanthrenes; Phenanthrolines; Salvia miltiorrhiza; TOR Serine-Threonine Kinases

The thunder god vine or Tripterygium wilfordii Hook. F. is a representative Chinese medicinal herb which has been used widely and successfully for centuries in treating inflammatory diseases. More than 100 components have been isolated from this plant, and most of them have potent therapeutic efficacy for a variety of autoimmune and inflammatory diseases. In the past four decades, the anticancer activities of the extracts from this medicinal herb have attracted intensive attention by researchers worldwide. The diterpenoid epoxide triptolide and the quinone triterpene celastrol are two important bioactive ingredients that show a divergent therapeutic profile and can perturb multiple signal pathways. Both compounds promise to turn traditional medicines into modern drugs. In this review, we will mainly address the anticancer activities and mechanisms of action of these two agents and briefly describe some other antitumor components of the thunder god vine.

Topics: Animals; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; Humans; Neoplasms; Pentacyclic Triterpenes; Phenanthrenes; Signal Transduction; Tripterygium; Triterpenes

Triptolide, a diterpenoid triepoxide, is the key biological component of Tripterygium wilfordii Hook. f. which was used in traditional Chinese medicine for centuries to treat inflammation and autoimmune diseases. Triptolide has shown potent activity in not only anti-inflammation and immune modulation, but also antiproliferative and proapoptotic activity in many different types of cancer cells. However, for a long time, the precise molecular target(s) of triptolide have remained elusive. Recently, several groups discovered that triptolide inhibited the activity of RNA polymerase. This review will focus on these breakthrough findings about the molecular target of triptolide and its implications for targeted-cancer therapeutics.

Topics: Animals; Cell Division; Diterpenes; DNA-Directed RNA Polymerases; Epoxy Compounds; Humans; Neoplasms; Oncogenes; Phenanthrenes

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

Triptolide, an epoxidated diterpene lactone compound separated from a traditional Chinese medicine, Tripterygium wilfordiiHook. f (TWHF), is responsible for the anti-tumor activity of TWHF with broad spectrum and high performance. The antitumor mechanism of triptolide locates in many fields, such as inducing apoptosis of tumor cell, interfering in the cell cycle, and suppressing angiogeneis. The advance in the anti-tumor mechanism of triptolide is described in the following review.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; Humans; Neoplasms; Phenanthrenes; Tripterygium

The aim of this review is to survey the various naturally occurring phenanthrene compounds that have been isolated from different plants. Only one review has previously been published on this topic. Gorham (1989) reviewed the structures, biosynthesis, separations and spectroscopy of stilbenes and phenanthrenes. The present study furnishes an overview of the hydroxy or/and methoxy-substituted 9,10-dihydro/phenanthrenes, methylated, prenylated and other monomeric derivatives, dimeric and trimeric phenanthrenes and their biological activities. A fairly large number of phenanthrenes have been reported from higher plants, mainly in the Orchidaceae family, in the species Dendrobium, Bulbophyllum, Eria, Maxillaria, Bletilla, Coelogyna, Cymbidium, Ephemerantha and Epidendrum. A few phenanthrenes have been found in the Hepaticae class and Dioscoreaceae, Combretaceae and Betulaceae families. Their distribution correlates strongly with the taxonomic divisions. These plants have often been used in traditional medicine, and phenanthrenes have therefore been studied for their cytotoxicity, antimicrobial, spasmolytic, anti-inflammatory, antiplatelet aggregation, antiallergic activities and phytotoxicity. On the basis of 120 references, this review covers the phytochemistry and pharmacology of phenanthrenes, describing 252 compounds. This contribution stems from our work on the medicinal plant Tamus communis.

Topics: Animals; Anti-Allergic Agents; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Bacteria; Biological Products; Cell Proliferation; Humans; Neoplasms; Parasympatholytics; Phenanthrenes; Platelet Aggregation; Platelet Aggregation Inhibitors

Along with the deep-going researches on mechanism of apoptosis, the apoptosis inducers as anticancer drugs have been the hot points of researches for new drugs. In this paper are reviewed a number of related articles on the progress in cell apoptosis inducers including the derivative anthraquinone, saponin, flavonids and terpines. The mechanisms are analyzed and discussed. The researches into the molecular mechanisms of inducer can provide the theoretical basis for discovering new compound, and can find out the apoptosis inducers with high efficiency and low toxicity. There is hope of developing apoptosis inducers into safe and effectual anticancer drugs.

Topics: Abietanes; Antineoplastic Agents; Apoptosis; Emodin; Flavones; Humans; Neoplasms; Phenanthrenes; Saponins

Recent progress in the field of DNA repair has demonstrated that transient inhibition of DNA damage detection or repair using potent poly(ADP-ribose) polymerase (PARP) inhibitors could improve the efficacy of cancer treatments. Although more study is needed, recent publications lead to optimism that the inhibition of poly(ADP-ribose) synthesis could selectively kill cancer cells when used to treat tumours with defective BRCA proteins. These reports and others shed some light on the DNA damage signalling and repair processes involving PARPs. However, a better understanding of the molecular mechanisms regulated by poly(ADP-ribose) metabolism will be essential before optimism can be replaced by clinical realization.

Topics: DNA Repair; Gene Components; Heterocyclic Compounds, 4 or More Rings; Humans; Indoles; Models, Molecular; Neoplasms; Phenanthrenes; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Quinazolines; Quinazolinones; Signal Transduction

Despite the age-old belief that most anti-cancer agents kill tumor cells by necrosis, recent findings have demonstrated that photosensitizers could also kill tumor cells by triggering genetically programmed series of events termed apoptosis. Cell death by apoptosis is a very neat way to eliminate unwanted cells: no traces are left and the cell contents are never released or accessible to the immune system. Hence there is no inflammation. This is in contrast to death by necrosis. Under these conditions, normally the cell swells and then, when membrane integrity comes under attack, the cell collapses like a balloon and the contents spill out into the extracellular milieu. This may result in an inflammatory response. Because of the relatively clean nature of the apoptotic process, it is desirable to identify compounds that effectively activate the apoptotic pathway. Photodynamic therapy (PDT), a new mode of treatment, is based on the combined use of light-absorbing compounds and light irradiation. Recent developments in understanding the mechanisms of the PDT effect of photosensitizers indicate that a critical factor in the success of the agent is the ability to induce apoptosis in the malignant cell population. Hypericin and Hypocrellins are perylquinones, which are novel natural photosensitizers characterized by high absorption around 470 nm and high singlet oxygen yield. To study the signaling mechanism in vitro we have investigated uptake kinetics, intracellular localization, mode of cell death and mechanisms involved in the photodynamic action following PDT in human cell lines of poorly differentiated (CNE2) and moderately differentiated (TW0-1) nasopharyngeal carcinoma (NPC) and also poorly differentiated colon (CCL-220.1) and bladder (SD) cells.

Topics: Apoptosis; Cell Death; Humans; Models, Biological; Neoplasms; Nitric Oxide; Perylene; Phenanthrenes; Photochemotherapy; Photosensitizing Agents; Phytotherapy; Quinones

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: Animals; Antineoplastic Agents; Arginase; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Deoxyribonucleases; DNA; Fluorouracil; Humans; Liver Neoplasms; Methylcholanthrene; Mice; Mutation; Neoplasms; Neoplasms, Experimental; Nucleosides; Oncogenic Viruses; Orotic Acid; Phenanthrenes; Protein Binding; Pyrimidinones; Rats; Skin Neoplasms; Thymine; Uracil

Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappaB. Therefore, compounds that inhibit NF-kappaB stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide.

Topics: Adult; Aged; Anemia; Antineoplastic Agents, Alkylating; Apoptosis; Diterpenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leukocytes; Male; Middle Aged; Neoplasms; Phenanthrenes

Use of natural products has been proposed as an efficient method in modulation of immune system and treatment of cancers. The aim of this study was to investigate the potential of cryptotanshinone (CPT), naringenin, and their combination in modulating the immune response towards Th1 cells and the involvement of JAK2/STAT3 signaling pathway in these effects.. Mouse models of delayed type hypersensitivity (DTH) were produced and treated with naringenin and CPT. The proliferation of spleen cells were assessed by Bromodeoxyuridine (BrdU) assay. Flowcytometry and enzyme-linked immunosorbent assay (ELISA) tests were employed to evaluate subpopulation of T-lymphocytes and the levels of cytokines, respectively. The JAK/STAT signaling pathway was analyzed by Western blotting.. We showed higher DTH, increased lymphocyte proliferation, decreased tumor growth and reduced JAK2/STAT3 phosphorylation in mice treated with naringenin and CPT. Moreover, a significant decline in the production of IL-4 and an upsurge in the production of IFN-γ by splenocytes were observed. Additionally, the population of intra-tumor CD4. Naringenin-CPT combination could exert immunomodulatory effects, suggesting this combination as a novel complementary therapeutic regimen for breast cancer.

Topics: Animals; Flavanones; Lymphocyte Activation; Mice; Neoplasms; Phenanthrenes; T-Lymphocytes, Regulatory

Although it is well established that human cytochrome P450 1 family enzymes are induced by cigarette smoking through activation of the Ah receptor, it is not known whether this leads to increased metabolic activation or detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAH), which are present in cigarette smoke and the general environment. We gave oral doses of deuterated phenanthrene ([D10]Phe), a non-carcinogenic surrogate of carcinogenic PAH such as benzo[a]pyrene, to smokers (N = 170, 1 or 10 μg doses) and non-smokers (N = 57, 1 μg dose). Bioactivation products (dihydrodiol and tetraol) and detoxification products (phenols) of [D10]Phe were determined in 6-h urine to obtain a comprehensive metabolic profile. Cigarette smoking increased the bioactivation of [D10]Phe and decreased its detoxification resulting in significantly different metabolic patterns between smokers and non-smokers (P < 0.01), consistent with increased cancer risk in smokers. The Phe bioactivation ratios ([D10]PheT/total [D9]OHPhe) were significantly higher (2.3 (P < 0.01) to 4.8 (P < 0.001) fold) in smokers than non-smokers. With solid human in vivo evidence, our results for the first time demonstrate that cigarette smoking enhances the metabolic activation of Phe, structurally representative of carcinogenic PAH, in humans, strongly supporting their causal role in cancers caused by smoking. The results suggest potential new methods for identifying smokers who could be at particularly high risk for cancer.

Topics: Carcinogenesis; Carcinogens; Cell Line, Tumor; Cigarette Smoking; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Neoplasms; Nicotiana; Phenanthrenes; Phenols; Polycyclic Aromatic Hydrocarbons; Receptors, Aryl Hydrocarbon

Several studies have highlighted both the extreme anticancer effects of Cryptotanshinone (CT), a Stat3 crippling component from Salvia miltiorrhiza, as well as other STAT3 inhibitors to fight cancer.. Data presented in this experiment incorporates 2 years of in vitro studies applying a comprehensive live-cell drug-screening analysis of human and canine cancer cells exposed to CT at 20 μM concentration, as well as to other drug combinations. As previously observed in other studies, dogs are natural cancer models, given to their similarity in cancer genetics, epidemiology and disease progression compared to humans.. Results obtained from several types of human and canine cancer cells exposed to CT and varied drug combinations, verified CT efficacy at combating cancer by achieving an extremely high percentage of apoptosis within 24 hours of drug exposure.. CT anticancer efficacy in various human and canine cancer cell lines denotes its ability to interact across different biological processes and cancer regulatory cell networks, driving inhibition of cancer cell survival.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Dogs; Early Detection of Cancer; Humans; Neoplasms; Phenanthrenes; Salvia miltiorrhiza; Signal Transduction; STAT3 Transcription Factor

The synthesis and characterization of a series of naphthalimide and phenanthro[9,10-d]imidazole conjugate is described. These compounds are evaluated in vitro for their cytotoxicity towards 60 human cancer cell lines. Derivative 16 shows excellent cytotoxic activity against these cancer cell lines with the range of growth inhibition from -55.78 to 94.53. The most potent derivative (ethylpiperazine, 16) is further studied to evaluate the interaction with ct-DNA using absorption and emission spectroscopy as well as DNA viscosity measurement. The DNA binding studies indicate that compound 16 is significantly interacted with DNA through groove binding having binding constant value of 7.81 × 10

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; DNA; DNA Topoisomerases, Type II; Drug Screening Assays, Antitumor; Humans; Imidazoles; Molecular Docking Simulation; Naphthalimides; Neoplasms; Phenanthrenes; Structure-Activity Relationship; Topoisomerase II Inhibitors

To identify status, source of polycyclic aromatic hydrocarbons (PAHs) in urban soils and to assess soil environmental quality in Xi'an City, China, total 45 soil samples were collected from surface layer (0-10 cm) in different functional areas. Total concentrations of 16 US EPA priority PAHs ranged from 149.9 to 5770 μg kg

Topics: Adolescent; Adult; Child; China; Chrysenes; Cities; Coal; Environmental Monitoring; Fluorenes; Humans; Industry; Neoplasms; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Pyrenes; Risk Assessment; Soil; Soil Pollutants; Vehicle Emissions

Dehydroeffusol (DHE) is a phenanthrene isolated from the Chinese medicinal plant Juncus effusus. Biological evaluation of DHE reveals in vitro and in vivo anticancer effects. We performed a shotgun proteomic analysis using liquid chromatography-tandem mass spectrometry to investigate the changes in the protein profiles in cancer cells upon DHE treatment. DHE affected cancer-associated signaling pathways, including NF-κB, β-catenin, and endoplasmic reticulum stress. Through quantitative pathway and key node analysis of the proteomics data, activating transcription factor 2 (ATF-2) and c-Jun kinase (JNK) were found to be the key components in DHE's modulated biological pathways. Based on the pathway analysis as well as chemical similarity to estradiol, DHE is proposed to be a phytoestrogen. The proteomic, bioinformatic, and chemoinformatic analyses were further verified with individual cell-based experiments. Our study demonstrates a workflow for identifying the mechanisms of action of DHE through shotgun proteomic analysis.

Topics: Activating Transcription Factor 2; Antineoplastic Agents; JNK Mitogen-Activated Protein Kinases; Neoplasms; Phenanthrenes; Phytochemicals; Phytoestrogens; Poaceae; Proteomics; Signal Transduction

Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examine the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalizes HRAS and KRAS from the PM with similar potency and disrupts the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization of cholera toxin, indicating suppression of recycling endosome function. In searching for the mechanism of impaired endosomal recycling we observed that G01 also enhanced cellular sphingomyelin (SM) and ceramide levels and disrupted the localization of several lipid and cholesterol reporters, suggesting that the G01 molecular target may involve SM metabolism. Indeed, G01 exhibited potent synergy with other compounds that target SM metabolism in KRAS localization assays. Furthermore, G01 significantly abrogated RAS-RAF-MAPK signaling in Madin-Darby canine kidney (MDCK) cells expressing constitutively activated, oncogenic mutant RASG12V. G01 also inhibited the proliferation of RAS-less mouse embryo fibroblasts expressing oncogenic mutant KRASG12V or KRASG12D but not RAS-less mouse embryo fibroblasts expressing oncogenic mutant BRAFV600E. Consistent with these effects, G01 selectively inhibited the proliferation of KRAS-transformed pancreatic, colon, and endometrial cancer cells. Taken together, these results suggest that G01 should undergo further evaluation as a potential anti-RAS therapeutic.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Dogs; Humans; Madin Darby Canine Kidney Cells; Mice; Neoplasms; Phenanthrenes; ras Proteins; Signal Transduction

Cancer remains a global health challenge. There is an urgent need to develop innovative therapeutics that can overcome the shortcomings of existing cancer therapies. DNA enzymes involved in nucleic acid compaction and organization are an attractive cancer drug target for therapeutic exploitation. In this work, a family of Cu(II) prodrugs containing suberoylanilide hydroxamic acid (SAHA), a well-established histone deacetylase inhibitor (HDACi) and clinically approved cancer drug, and phenanthrene ligands as DNA intercalative components have been rationally developed. The complexes, of general formula [Cu(SAHA

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Copper; DNA; DNA Damage; Histone Deacetylase Inhibitors; Humans; Intercalating Agents; Neoplasms; Organometallic Compounds; Oxidative Stress; Phenanthrenes; Prodrugs; Vorinostat

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Diterpenes; Doxorubicin; Drug Delivery Systems; Drug Synergism; Epoxy Compounds; Flow Cytometry; Humans; Lactic Acid; Lipids; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Oxidation-Reduction; Particle Size; Phenanthrenes; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Cellular senescence, an irreversible growth arrest of cells, is involved in protection against cancer. Triptolide (TPL) plays an important role in immunosuppressive, anti-fertility, anti-cystogenesis and anticancer activities. However, effect and mechanism of TPL on cellular senescence-associated antitumor is rarely reported. Herein HepG2 cells were used to explore the effect of TPL on tumor growth and cellular senescence. We showed that TPL inhibited tumor cell proliferation and growth in vitro and in vivo, accelerated cellular senescence and arrested cells at G0/G1 phase. We further demonstrated that TPL accelerated HepG2 cell senescence by regulating the AKT pathway. In addition, TPL could also enhance cellular senescence and inhibit tumor growth by negatively regulating human telomerase reverse transcriptase (hTERT) signaling pathway. These findings reveal a regulatory mechanism of TPL on cellular senescence, indicating that TPL promotes HepG2 cell senescence through AKT pathway and hTERT pathway simultaneously. Altogether, TPL-induced senescence can be regarded as a promising strategy for anticancer therapy and drug development.

Topics: Animals; Cell Proliferation; Cellular Senescence; Diterpenes; Epoxy Compounds; Hep G2 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Phenanthrenes; Signal Transduction; Up-Regulation; Xenograft Model Antitumor Assays

Cryptotanshinone (CPT), a fat-soluble phenanthraquinone from Salvia miltiorrhiza Bunge, has been demonstrated to inhibit phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), a couple of direct downstream effectors of the mammalian target of rapamycin complex 1 (mTORC1), resulting in cancer cell arrested in G0 phase and subsequent inhibition of proliferation. However, its concrete molecular mechanism about how CPT inhibits mTORC1 signaling pathway is unclear.. one solution was used to check cell viability and western blotting for determining expression of the indicated proteins. Molecular docking was performed to assess the binding of CPT with mTOR. The co-immunoprecipitation assay was to analyze whether CPT could disrupt the mTORC1 and TSC1/TSC2 complex. Recombinant adenoviral dominant-negative AMPKα was used to downregulate expression of AMPKα and lentiviral AMPK and TSC2 to silence the AMPK and TSC2 in Rh30 cells.. Primarily, Rh30 cells expressing rapamycin-resistant mutant mTOR are also sensitive to CPT, while the molecular docking result for CPT binding to mTOR is negative, suggesting that CPT inhibition of mTORC1 is different from rapamycin. Then the related proteins of PTEN-PI3K pathway was proved not to be affected, but the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was activated by a concentration- and time- dependent manner, meaning that it may be associated with AMPK. Further results indicated that compound C, inhibitor of AMPK, could clearly reversed CPT inhibitory effect on Rh30 cells, and dominant-negative AMPK in cancer cells conferred resistance to CPT inhibition of 4E-BP1 and phosphorylation of S6K1, as well as sh-AMPK. Furthermore, compared with AMPK-positive MEF cells, AMPK-negative MEF cells are less sensitive to CPT by the findings that 4E-BP1 and phosphorylation of S6K1 express comparatively more. Additionally, phosphorylation of tuberous sclerosis complex 2 (TSC2) was activated under the treatment of CPT, and down-expression of TSC2 by shRNA slightly recovered expression of 4E-BP1 and phosphorylation of S6K1, while co-immunoprecipitation of TSC2 did not alter expression of TSC1 by CPT.. CPT inhibiting mTORC1 pathway was mostly due to activation of AMPK-TSC2 axis rather than specific binding to mTORC1. CPT is a potent anticancer agent targeting AMPK.

Topics: Adenylate Kinase; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mechanistic Target of Rapamycin Complex 1; Neoplasms; Phenanthrenes; Phosphorylation; Signal Transduction; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

We identified target proteins modified by phenanthrenes that cause exclusive eradication of human cancer cells. The cytotoxic activity of the phenanthrenes in a variety of human cancer cells is attributed by these findings to post translational modifications of NuMA and kinesins HSET/kifC1 and kif18A. Their activity prevented the binding of NuMA to α-tubulin and kinesins in human cancer cells, and caused aberrant spindles. The most efficient cytotoxic activity of the phenanthridine PJ34, caused significantly smaller aberrant spindles with disrupted spindle poles and scattered extra-centrosomes and chromosomes. Concomitantly, PJ34 induced tumor growth arrest of human malignant tumors developed in athymic nude mice, indicating the relevance of its activity for cancer therapy.

Topics: Animals; Antigens, Nuclear; Apoptosis; Biomarkers, Tumor; Cell Cycle Proteins; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Kinesins; Mice; Mitosis; Neoplasms; Nuclear Matrix-Associated Proteins; Phenanthrenes; Protein Processing, Post-Translational; Spindle Apparatus; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Cryptotanshinone (CT), one major lipophilic component isolated from Salvia miltiorrhiza Bunge, has shown to possess chemopreventive properties against various types of cancer cells. In this study, CT was shown to be a potent anti-angiogenic agent in zebrafish, and mouse models and could limit tumor growth by inhibiting tumor angiogenesis. We further found that CT could inhibit the proliferation, migration, angiogenic sprouting, and tube formation of HUVECs. In addition, we demonstrated that CT could lower the level of TNF-α due to the destabilization of TNF-α mRNA, which associated with regulating 3'-untranslated region (3'-UTR) of TNF-α and preventing the translocation of RNA binding protein, HuR, from the nucleus to the cytoplasm. Moreover, the underlying mechanism responsible for the regulation in angiogenesis by CT was partially related to the suppression of NF-κB, and STAT3 activity. Based on the abilities of CT in targeting tumor cells, inhibiting angiogenesis, and destroying tumor vasculature, CT is worthy of further investigation for preventive, and therapeutic purposes in cancer. © 2015 Wiley Periodicals, Inc.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Cytoplasm; ELAV-Like Protein 1; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Mice; Neoplasms; Phenanthrenes; RNA Stability; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays; Zebrafish

Bioactivity guided phytochemical investigation of the ethanol extract of the medullae of Juncus effusus resulted in the isolation of two new phenanthrenes, 8-hydroxymethyl-2-hydroxyl-1-methyl-5-vinyl-9,10-dihydrophenanthrene (1), and 5-(1-methoxyethyl)-1-methyl-phenanthren-2,7-diol (2) together with 15 known phenanthrenoids (3-17). The chemical structures of 1 and 2 were established by a combination of spectroscopic techniques. Compounds 1-15 and 17 were evaluated for their cytotoxic activities against five human cancer cell lines (SHSY-5Y, SMMC-7721, HepG-2, Hela and MCF-7) by CCK-8 assay, and their anti-inflammatory activities were also evaluated by inhibition on NO production in LPS-activated murine macrophage RAW 264.7 cells.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Cell Survival; Dose-Response Relationship, Drug; HeLa Cells; Hep G2 Cells; Humans; Inhibitory Concentration 50; Macrophage Activation; Macrophages; Magnoliopsida; MCF-7 Cells; Mice; Molecular Structure; Neoplasms; Nitric Oxide; Phenanthrenes; Phytotherapy; Plant Extracts; Plants, Medicinal; RAW 264.7 Cells; Structure-Activity Relationship

Triptolide, a key ingredient from the traditional Chinese medicinal plant thunder god vine, which has been used to treat inflammation and autoimmune diseases for centuries, has been shown to be an irreversible inhibitor of the XPB subunit of the transcription factor TFIIH and initiation of RNA polymerase II mediated transcription. The clinical development of triptolide over the past two decades has been limited by its toxicity and low water solubility. Herein, we report the development of a glucose conjugate of triptolide, named glutriptolide, which was intended to target tumor cells overexpressing glucose transporters selectively. Glutriptolide did not inhibit XPB activity in vitro but demonstrated significantly higher cytotoxicity against tumor cells over normal cells with greater water solubility than triptolide. Furthermore, it exhibited remarkable tumor control in vivo, which is likely due to sustained stepwise release of active triptolide within cancer cells. These findings indicate that glutriptolide may serve as a promising lead for developing a new mechanistic class of anticancer drugs.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Diterpenes; Drug Delivery Systems; Epoxy Compounds; Glucose; HEK293 Cells; Humans; Mice; Neoplasms; Phenanthrenes

The concentrations, distribution, possible sources, and cancer risks of polycyclic aromatic hydrocarbons (PAHs) in total suspended particles (TSPs) and surface soils collected from the same sampling spots were compared in Kunming, China. The total PAH concentrations were 9.35-75.01 ng/m(3) and 101.64-693.30 ng/g dry weight (d.w.), respectively, in TSPs and surface soils. Fluoranthene (FLA), pyrene (PYR), chrysene (CHR), and phenanthrene (PHE) were the abundant compounds in TSP samples, and phenanthrene (PHE), fluorene (FLO), fluoranthene (FLA), benzo[b]fluoranthene (BbF), and benzo[g,h,i]perylene (BghiP) were the abundant compounds in surface soil samples. The spatial distribution of PAHs in TSPs is closely related to the surrounding environment, which varied significantly as a result of variations in source emission and changes in meteorology. However, the spatial distribution of PAHs in surface soils is supposed to correlate with a city's urbanization history, and high levels of PAHs were always observed in industry district, or central or old district of city. Based on the diagnostic ratios and principal component analysis (PCA), vehicle emissions (especially diesel-powered vehicles) and coal and wood combustion were the main sources of PAHs in TSPs, and the combustion of wood and coal, and spills of unburnt petroleum were the main sources of PAHs in the surface soils. The benzo[a]pyrene equivalent concentration (BaPeq) for the TSPs and surface soil samples were 0.16-2.57 ng/m(3) and 11.44-116.03 ng/g d.w., respectively. The incremental lifetime cancer risk (ILCR) exposed to particulate PAHs ranged from 10(-4) to 10(-3) indicating high potential of carcinogenic risk, and the ILCR exposed to soil PAHs was from 10(-7) to 10(-6) indicating virtual safety. These presented results showed that particle-bound PAHs had higher potential carcinogenic ability for human than soil PAHs. And, the values of cancer risk for children were always higher than for adults, which demonstrated that children were sensitive to carcinogenic effects of PAHs.

Topics: Air Pollutants; Benzo(a)pyrene; Carcinogens; China; Chrysenes; Cities; Coal; Fluorenes; Fluorine; Humans; Neoplasms; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Principal Component Analysis; Pyrenes; Risk Assessment; Soil; Soil Pollutants; Vehicle Emissions

Tylophorine compounds have been the focus of drug development for decades. Tylophorine derivatives exhibit anti-cancer activities but their cellular targets remain unknown. We used a biotinylated tylophorine derivative to probe for the interacting cellular target(s) of tylophorine. Tylophorine directly binds to caprin-1 and consequently enhances the recruitment of G3BP1, c-Myc mRNA, and cyclin D2 mRNA to form a ribonucleoprotein complex. Subsequently, this tylophorine targeted ribonucleoprotein complex is sequestered to the polysomal fractions and the protein expressions of the associated mRNA-transcripts are repressed. Caprin-1 depleted carcinoma cells become more resistant to tylophorine, associated with decreased formation of the ribonucleoprotein complex targeted by tylophorine. Consequently, tylophorine downregulates c-Myc and cyclins D1/D2, causing hypophosphorylation of Rb and suppression of both processing-body formation and the Warburg effect. Gene expression profiling and gain-of-c-Myc-function experiments also revealed that the downregulated c-Myc contributes to the anti-oncogenic effects of tylophorine compounds. Furthermore, the potent tylophorine derivative dibenzoquinoline-33b elicited a similar effect, as c-Myc protein levels were also decreased in xenograft tumors treated with dibenzoquinoline-33b. Thus, tylophorine compounds exert anti-cancer activity predominantly by targeting and sequestering the caprin-1 protein and c-Myc mRNA associated ribonucleoprotein complex.

Topics: Alkaloids; Animals; Blotting, Western; Carrier Proteins; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Cyclin D2; DNA Helicases; HEK293 Cells; HeLa Cells; Hep G2 Cells; Humans; Indolizines; MCF-7 Cells; Mice; Multiprotein Complexes; Neoplasms; Phenanthrenes; Poly-ADP-Ribose Binding Proteins; Protein Binding; Proto-Oncogene Proteins c-myb; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleoproteins; RNA Helicases; RNA Interference; RNA Recognition Motif Proteins; RNA, Messenger; Tumor Burden; U937 Cells; Xenograft Model Antitumor Assays

eIF4E binding protein 1 (4E-BP1), is critical for cap-dependent and cap-independent translation. This study is the first to demonstrate that 4E-BP1 expression correlates with colorectal cancer (CRC) progression. Compared to its expression in normal colon epithelial cells, 4E-BP1 was upregulated in CRC cell lines and was detected in patient tumor tissues. Furthermore, high 4E-BP1 expression was statistically associated with poor prognosis. Hypoxia has been considered as an obstacle for cancer therapeutics. Our previous data showed that YXM110, a cryptopleurine derivative, exhibited anticancer activity via 4E-BP1 depletion. Here, we investigated whether YXM110 could inhibit protein synthesis under hypoxia. 4E-BP1 expression was notably decreased by YXM110 under hypoxic conditions, implying that cap-independent translation could be suppressed by YXM110. Moreover, YXM110 repressed hypoxia-inducible factor 1α (HIF-1α) expression, which resulted in decreased downstream vascular endothelial growth factor (VEGF) expression. These observations highlight 4E-BP1 as a useful biomarker and therapeutic target, indicating that YXM110 could be a potent CRC therapeutic drug.

Topics: Adaptor Proteins, Signal Transducing; Alkaloids; Antineoplastic Agents; Caco-2 Cells; Cell Cycle Proteins; Cell Line, Tumor; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Neoplasms; Phenanthrenes; Phosphoproteins; Prognosis; Protein Biosynthesis; Quinolizidines; Treatment Outcome; Vascular Endothelial Growth Factor A

Tumor-associated angiogenesis is triggered by multiple angiogenic factors. Vascular endothelial growth factor blockers are currently a major mechanism of angiogenesis inhibition; however, either insensitivity due to the targeting of single angiogenic factors or serious side effects due to non-specific exposure ultimately leads to the failure of treatment. The herb-derived compound triptolide (TP) can inhibit tumor growth through multiple mechanisms. However, its hydrophobicity and side effects have hindered its translation to the clinic. Here, we have prepared TP-polymeric micelles (TP-PMs) using methoxy poly(ethylene glycol)-block-poly(ε-caprolactone). The drug loading efficiency and encapsulation efficiency can reach 7.2 ± 0.10% and 99.1 ± 1.05%, respectively. The TP-PM solution consisted of monodispersed particles (PDI = 0.100 ± 0.023), which were 53.1 ± 1.2 nm in size. In vitro release profiles indicated that the TP-PM solution exhibited better sustained-release action when compared with free TP solution. Pharmacokinetic and tumor tissue distribution studies showed that TP-PMs facilitated TP accumulation in tumor tissues. The tumor inhibition rate upon treatment with TP-PMs was higher than 50%, and the survival time of B16-F10 melanoma bearing mice was efficiently prolonged after TP-PM administration. In addition, serum VEGF levels and tumor incidence of the TP-PM-treated group were both significantly reduced, and histological analyses revealed that the tumor vessel diameter and density in the TP-PM-treated group were much smaller than those observed in the control groups. These results indicated that TP-PMs serve as a potential angiogenesis inhibitor.

Topics: Animals; Antineoplastic Agents, Alkylating; Cells, Cultured; Diterpenes; Drug Carriers; Epoxy Compounds; Human Umbilical Vein Endothelial Cells; Humans; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Neovascularization, Pathologic; Phenanthrenes; Rats; Rats, Sprague-Dawley

Triptolide and celastrol are two main active compounds isolated from Thunder God Vine with the potent anticancer activity. However, the anticancer effect of triptolide in combination with celastrol is still unknown. In the present study, we demonstrated that the combination of triptolide with celastrol synergistically induced cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the increased intracellular ROS accumulation in cancer cells. Pretreatment with ROS scavenger N-acetyl-L-cysteine dramatically blocked the apoptosis induced by co-treatment with triptolide and celastrol. Treatment with celastrol alone led to the decreased expressions of HSP90 client proteins including survivin, AKT, EGFR, which was enhanced by the addition of triptolide. Additionally, the celastrol-induced expression of HSP70 and HSP27 was abrogated by triptolide. In the nude mice with xenograft tumors, the lower-dose combination of triptolide with celastrol significantly inhibited the growth of tumors without obvious toxicity. Overall, triptolide in combination with celastrol showed outstanding synergistic anticancer effect in vitro and in vivo, suggesting that this beneficial combination may offer a promising treatment option for cancer patients.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Diterpenes; Dose-Response Relationship, Drug; Drug Synergism; Epoxy Compounds; G2 Phase Cell Cycle Checkpoints; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Mice, Inbred BALB C; Mice, Nude; Molecular Chaperones; Neoplasms; Pentacyclic Triterpenes; Phenanthrenes; Phytotherapy; Plant Extracts; Plants, Medicinal; Reactive Oxygen Species; Time Factors; Transfection; Tripterygium; Triterpenes; Tumor Burden; Xenograft Model Antitumor Assays

Most bone-related diseases are characterized by excessive bone resorption by osteoclasts. Receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) has emerged as a major mediator of bone resorption, commonly associated with cancer and chronic inflammatory diseases. Thus inhibitors of RANKL signaling have a potential in preventing bone loss. In the present study, we investigated the ability of triptolide, a diterpenoid isolated from Thunder of God Vine, to inhibit signaling by receptor activator of NF-κB (RANK) and its ligand (RANKL) and to modulate osteoclastogenesis induced by RANKL and human cancer cells. We found that triptolide suppressed RANKL-induced differentiation of precursor cells to osteoclasts, and also inhibited osteoclast formation induced by human breast tumor cells (MDA-MB-231), multiple myeloma cells (U266) and prostate tumor cells (PC-3). Triptolide inhibited RANKL-induced NF-κB activation in osteoclast precursor cells by inhibiting IκBα kinase activation, IκBα phosphorylation, and IκBα degradation. Our results suggest that triptolide effectively inhibits RANKL-induced NF-κB activation and RANKL- and tumor cell-induced osteoclastogenesis. This warrants further study of triptolide as a potential therapy for osteoporosis and cancer-associated bone loss.

Topics: Animals; Bone Resorption; Cell Differentiation; Cell Line, Tumor; Diterpenes; Epoxy Compounds; Humans; Mice; Neoplasms; Osteoclasts; Osteoporosis; Phenanthrenes; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclic N-Oxides; Disease Models, Animal; Diterpenes; Drug Resistance, Neoplasm; Drug Synergism; Epoxy Compounds; Female; Gene Dosage; Humans; Indolizines; Male; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Phenanthrenes; Pyridinium Compounds; RNA, Messenger; Sulfonamides; Xenograft Model Antitumor Assays

Brassica rapa ssp. campestris (Brassicaceae) is a conical, deep purple, edible root vegetable commonly known as a turnip. We initiated phytochemical and pharmacological studies to search for biological active compounds from the roots of B. rapa ssp. campestris. We isolated a novel phenanthrene derivative, 6-methoxy-1-[10-methoxy-7-(3-methylbut-2-enyl)phenanthren-3-yl]undecane-2,4-dione, named brassicaphenanthrene A (3) along with two known diarylheptanoid compounds, 6-paradol (1) and trans-6-shogaol (2), through the repeated silica gel (SiO2), octadecyl silica gel, and Sephadex LH-20 column chromatography. The chemical structures of the compounds were determined by spectroscopic data analyses including nuclear magnetic resonance, mass spectrometry, ultraviolet spectroscopy, and infra-red spectroscopy. All compounds exhibited high inhibitory activity against the growth of human cancer lines, HCT-116, MCF-7, and HeLa, with IC50 values ranging from 15.0 to 35.0 μM and against LDL-oxidation with IC50 values ranging from 2.9 to 7.1 μM.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Brassica rapa; Cell Proliferation; Diarylheptanoids; Dose-Response Relationship, Drug; HCT116 Cells; HeLa Cells; Humans; Inhibitory Concentration 50; Lipoproteins, LDL; Magnetic Resonance Spectroscopy; Mass Spectrometry; MCF-7 Cells; Molecular Structure; Neoplasms; Phenanthrenes; Phytotherapy; Plant Roots; Plants, Medicinal; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

Natural products have always been a profuse database for developing new chemotherapeutics. YXM110 is a newly synthesized phenanthroquinolizidines that exhibits excellent anticancer activity in numerous cancer cells. In this study, we examined the anticancer mechanisms of YXM110 both in vitro and in vivo. Protein level of 4E-binding protein 1, which is crucial in cap-independent translation, was decreased significantly after YXM110 treatment via c-Jun N-terminal kinases-mediated proteasomal degradation. Moreover, the effects of YXM110 were associated with several characteristics of autophagy, including accumulation of autophagic vacuoles, elevation of Atg12-Atg5 and light chain 3 (LC3)-II, and levels of GFP-LC3 puncta. The results suggested that depletion of Mcl-1 contributes to YXM110-triggered autophagy, whereas downregulation of lysosomal-related genes could cause autophagy impairment. Furthermore, YXM110-induced cell death was prevented by autophagy inhibitor 3-methyladenine and Atg5 silencing, indicating that YXM110-mediated autophagy impairment leads to cancer cell death. These data reveal key mechanisms that support the further development of YXM110 as a promising anticancer agent.

Topics: Adaptor Proteins, Signal Transducing; Alkaloids; Antineoplastic Agents; Apoptosis; Autophagy; Cell Cycle Proteins; Cell Proliferation; Cell Survival; HCT116 Cells; Humans; JNK Mitogen-Activated Protein Kinases; Microtubule-Associated Proteins; Neoplasms; Phenanthrenes; Phosphoproteins; Quinolizidines; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Natural compounds isolated from medicinal plants are invaluable resources for drug discovery. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent unique by its cancer cell-specific proapoptotic action, but its potential is heavily curbed by acquired resistance. We herein reported for the first time the identification of cytotoxic and TRAIL-sensitizing components of Salvia miltiorrhiza (Danshen), a traditional medicinal plant effective for treating cardiovascular disorders. Specifically, we found that the ethanol extract and its group 5 fraction of S. miltiorrhiza showed evident cytotoxicity against the human lung adenocarcinoma cell line A549 and ovarian adenocarcinoma cell line TOV-21G in a concentration-dependent manner. Likewise, a dose-dependent cytotoxicity was exerted by the standard solutions of cryptotanshinone, tanshinone I and tanshinone IIA, the major components of the group 5 fraction, where tanshinone IIA were most potent and displayed an IC₅₀ of 2.00 ± 0.36 μM and 2.75 ± 0.23 μM for A549 and TOV-21G, respectively. Induction of apoptosis represents an essential mechanism underlying tanshinone IIA-mediated cytotoxic action, as evidenced by the proteolytic processing of PARP upon tanshinone IIA stimulation and, importantly, a marked rescue of the viability of tanshinone IIA-treated cells when co-treatment with the pan-caspase inhibitor z-VAD-fmk. Noteworthy, stimulation with cryptotanshinone, tanshinone I or tanshinone IIA all effectively potentiated TRAIL to reduce viability and inhibit the colony formation capacity of TRAIL-resistant TOV-21G and SKOV3. Collectively, we revealed the proapoptotic and TRAIL-sensitizing components of S. miltiorrhiza and further implicated the potential of developing these active compounds as monotherapeutic agent or TRAIL-based therapy for cancer chemoprevention or chemotherapy.

Topics: Abietanes; Amino Acid Chloromethyl Ketones; Apoptosis; Caspase Inhibitors; Cell Division; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Humans; Inhibitory Concentration 50; Neoplasms; Phenanthrenes; Phenanthrolines; Plant Extracts; Poly(ADP-ribose) Polymerases; Salvia miltiorrhiza; TNF-Related Apoptosis-Inducing Ligand

In this study, the concentrations of polycyclic aromatic hydrocarbons (PAHs) in soil profiles and the soil properties were analyzed in Hunpu, a typical wastewater irrigation area, northeast of China. The total concentrations of 16 priority control PAHs ranged from 7.88 to 2,231.42 μg/kg. Among 16 PAHs, the most abundant was Phenanthrene and the 3- or 4- ring PAHs were predominant. The PAH concentrations were higher in the upland fields near the oil wells, whereas leaching of PAH into the groundwater caused low concentrations in the paddy fields. The geochemical indices and the results from the principal component analysis of all 16 PAHs indicated that PAHs were mainly from atmospheric dusts in the top soil in I-1P/I-3P/I-7P and through soil profiles in I-4U/I-5P/I-8U, whereas those in the bottom layers were mainly from petroleum production and wastewater irrigation in I-1P/I-3P/I-7P and through soil profiles in I-2U and I-6U. In the redundancy analysis, PAHs exhibited negative correlation with pH, depth, silt, and clay, but had positive correlation with sand and organic matter. Finally, total toxic equivalent in the soil profiles and the calculated health risk of PAHs in the surface soil using contaminated land exposure assessment model elucidated the cancer risk that PAHs pose on human health in the Hunpu region.

Topics: Air Pollutants; China; Environmental Exposure; Humans; Neoplasms; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Risk Assessment; Soil; Soil Pollutants; Wastewater; Water Pollutants, Chemical

9,10-Phenanthrenequinone (9,10-PQ) is one of the most abundant quinones among diesel exhaust particulates. Recent data have suggested that quinones induce apoptosis in immune, epithelial and tumor cells, leading to respirator illness; however, the mechanisms by which quinones induce apoptosis and the structure required for this remain unknown. We studied the antitumor activity of 9,10-PQ analogs against two human tumor cell lines, HCT-116 colon tumor cells and HL-60 promyelocytic leukemia cells. The loss of the cis-orthoquinone unit in 9,10-PQ abrogated its ability to induce apoptosis in the two tumor cell lines, and the LC50 values of these analogs were indicated over 10 μM. An analog of 9,10-PQ in which the biaryl unit had been deleted displayed a reduced ability to induce tumor cell apoptosis, while the analogs 1,10-phenanthroline-5,6-dione (9) and pyrene-4,5-dione (10), which also had modified biaryl units, exhibited increased tumor cell apoptotic activity. The cis-orthoquinone unit in 9,10-PQ was identified as essential for its ability to induce apoptosis in tumor cells, and its biaryl unit is also considered to influence orthoquinone-mediated apoptotic activity.

Topics: Antineoplastic Agents; Apoptosis; HCT116 Cells; HL-60 Cells; Humans; Inhibitory Concentration 50; Molecular Structure; Neoplasms; Phenanthrenes

Anti-angiogenesis targeting VEGFR2 has been considered as an important strategy for cancer therapy. Tylophorine is known to possess anti-inflammatory and antitumor activity, but its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro and in vivo.. We used tylophorine and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro and Ehrlich ascites carcinoma (EAC) tumor in vivo.. Tylophorine significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR2 tyrosine kinase activity and its downstream signaling pathways including Akt, Erk and ROS in endothelial cells. Using HUVECs we demonstrated that tylophorine inhibited VEGF-stimulated inflammatory responses including IL-6, IL-8, TNF-α, IFN-γ, MMP-2 and NO secretion. Tylophorine significantly inhibited neovascularization in sponge implant angiogenesis assay and also inhibited tumor angiogenesis and tumor growth in vivo. Molecular docking simulation indicated that tylophorine could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit.. Tylophorine exerts anti-angiogenesis effects via VEGFR2 signaling pathway thus, may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies.

Topics: Alkaloids; Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Cell Movement; Cell Proliferation; Cell Survival; Cytokines; Disease Models, Animal; Female; Human Umbilical Vein Endothelial Cells; Humans; Indolizines; Male; Matrix Metalloproteinase 2; Mice; Molecular Conformation; Molecular Docking Simulation; Neoplasms; Neovascularization, Physiologic; Nitric Oxide; Phenanthrenes; Protein Binding; Protein Interaction Domains and Motifs; Signal Transduction; Tumor Burden; Tylophora; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Angiogenesis is essential for the survival and growth of most tumors. As such, targeting the tumor neovasculature is an attractive strategy for effective cancer therapy. Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. The functional domain within amino acid residues 120-180 of vasostatin (VAS) has been confirmed to be effective in inhibiting the proliferation, migration, and invasiveness of cancer cells by its suppressive capacity against angiogenesis. Triptolide (TPL) is an active component extracted from the traditional Chinese herbal medicine Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic antitumor activity of TPL and VAS in solid tumor cells. Our results showed that the sensitivity of combined therapy using TPL and VAS was higher than that of monotherapy using TPL or VAS. Apoptosis induced by the combined treatment was accompanied by activation of caspase-9, caspase-8, and caspase-3. Upregulation of proapoptotic protein (Bax, Bak, and Bad) expression and suppression of NF-κB transcriptional activity and its targeting antiapoptotic genes (c-FLIP, cIAP, Bcl-2, Bcl-xl, and Mcl-1) may contribute to the synergistic effects of this combination therapy. Further, using a mouse xenograft model, we demonstrated that combined treatment completely suppressed tumor growth as compared with treatment with TPL or VAS alone. These results suggest that the combination of TPL and VAS at lower concentrations may produce a synergistic antitumor effect that warrants further investigation for its potential clinical applications.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Calreticulin; Cell Line; Cell Line, Tumor; Colorectal Neoplasms; Diterpenes; Drug Synergism; Drugs, Chinese Herbal; Epoxy Compounds; Ethnopharmacology; HCT116 Cells; Humans; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Phenanthrenes; Random Allocation; Recombinant Proteins; Tripterygium; Xenograft Model Antitumor Assays

A chemical investigation of the EtOAc-soluble fraction from the ethanol extract of the medullae of Juncus effusus led to the isolation of three new 9,10-dihydrophenanthrenes, juncuenins E-G (1-3); two new phenanthrenes, dehydrojuncuenins D-E (4-5); one new feruloylated glycoside (6); and one known 9,10-dihydrophenanthrene (7). The structures of these compounds were determined by analyzing their spectroscopic data. Metabolites 1-4 and 7 were further evaluated for their in vitro cytotoxic activities against seven human cancer lines (A549, MCF-7, BEL-7402, HeLa, COLO205, BGC-823, and SK-OV-3). Among them, compound 1 exhibited weak cytotoxicity against MCF-7 and HeLa cell lines. Compound 7 showed moderate cytotoxicity against MCF-7 and HeLa cell lines, with IC50 values of 9.17 and 19.6 µM, respectively.

Topics: Antineoplastic Agents, Phytogenic; HeLa Cells; Humans; Magnoliopsida; MCF-7 Cells; Molecular Structure; Neoplasms; Phenanthrenes; Phytotherapy; Plant Extracts

Preclinical and clinical trials demonstrated that use of oncolytic viruses (OVs) is a promising new therapeutic approach to treat multiple types of cancer. To further improve their viral oncolysis, experimental strategies are now combining OVs with different cytotoxic compounds. In this study, we investigated the capacity of triptolide - a natural anticancer molecule - to enhance vesicular stomatitis virus (VSV) oncolysis in OV-resistant cancer cells. Triptolide treatment increased VSV replication in the human prostate cancer cell line PC3 and in other VSV-resistant cells in a dose- and time-dependent manner in vitro and in vivo. Mechanistically, triptolide (TPL) inhibited the innate antiviral response by blocking type I interferon (IFN) signaling, downstream of IRF3 activation. Furthermore, triptolide-enhanced VSV-induced apoptosis in a dose-dependent fashion in VSV-resistant cells, as measured by annexin-V, cleaved caspase-3, and B-cell lymphoma 2 staining. In vivo, using the TSA mammary adenocarcinoma and PC3 mouse xenograft models, combination treatment with VSV and triptolide delayed tumor growth and prolonged survival of tumor-bearing animals by enhancing viral replication. Together, these results demonstrate that triptolide inhibition of IFN production sensitizes prostate cancer cells to VSV replication and virus-mediated apoptosis.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Line, Tumor; Combined Modality Therapy; Diterpenes; Epoxy Compounds; Female; HEK293 Cells; Humans; Interferons; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neoplasms, Experimental; Oncolytic Virotherapy; Oncolytic Viruses; Phenanthrenes; Signal Transduction; Vesicular stomatitis Indiana virus; Virus Replication; Xenograft Model Antitumor Assays

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells but not normal cells. However, TRAIL resistance due to low level of TRAIL receptor expression is widely found in cancer cells and hampers its development for cancer treatment. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are urgently needed. We investigated whether tanshinones, the major bioactive compounds of Salvia miltiorrhiza (danshen), can up-regulate TRAIL receptor expression. Among the major tanshinones being tested, cryptotanshinone (CT) showed the best ability to induce TRAIL receptor 2 (DR5) expression. We further showed that CT was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. CT-induced DR5 induction was not cell type-specific, as DR5 induction was observed in other cancer cell types. DR5 knockdown abolished the enhancing effect of CT on TRAIL responses. Mechanistically, induction of the DR5 by CT was found to be p53-independent but dependent on the induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). Knockdown of CHOP abolished CT-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, CT-induced ROS production preceded up-regulation of CHOP and DR5 and consequent sensitization of cells to TRAIL. Interestingly, CT also converted TRAIL-resistant lung A549 cancer cells into TRAIL-sensitive cells. Taken together, our results indicate that CT can potentiate TRAIL-induced apoptosis through up-regulation of DR5.

Topics: Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Drugs, Chinese Herbal; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Neoplasms; Phenanthrenes; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Salvia miltiorrhiza; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Up-Regulation

A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere-derived intramolecular G-quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G-quadruplexes from sequences based on the human telomeric repeat (TTAGGG)(n). The greatest stabilization was observed for the p-chlorophenyl derivative 6((G4)DC(50) =0.31 μM). We also show that the G-quadruplex binding complexes are able to inhibit telomerase activity through a modified telomerase repeat amplification protocol (TRAP-LIG assay). Preliminary cell studies show that complex 6 is preferentially cytotoxic toward cancer over normal cell lines, indicating its potential use in cancer therapy.

Topics: Antineoplastic Agents; Base Sequence; Cell Line; Cell Line, Tumor; Circular Dichroism; DNA; G-Quadruplexes; Humans; Models, Molecular; Neoplasms; Organoplatinum Compounds; Phenanthrenes; Telomere

PPM1D is a p53-inducible Ser/Thr protein phosphatase. PPM1D gene amplification and overexpression have been reported in a variety of human tumors, including breast cancer and neuroblastoma. Because the phosphatase activity of PPM1D is essential for its oncogenic role, PPM1D inhibitors should be viable anti-cancer agents. In our current study, we showed that SPI-001 was a potent and specific PPM1D inhibitor. SPI-001 inhibited PPM1D phosphatase activity in PPM1D-overexpressing human breast cancer cells and increased phosphorylation of p53. Furthermore, SPI-001 suppressed cell proliferation by inducing apoptosis. Our present study suggested that SPI-001 was a potential lead compound in developing anti-cancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Dose-Response Relationship, Drug; Humans; Indoles; Inhibitory Concentration 50; Models, Chemical; Neoplasms; Phenanthrenes; Phosphoprotein Phosphatases; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Phosphatase 2C; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins pp60(c-src); Time Factors; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells.

Topics: Antineoplastic Agents, Phytogenic; Caspases; Cell Death; Cell Line, Tumor; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasms; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Up-Regulation

Retinoid X receptor-alpha (RXRα) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRα resulted in production of a truncated product, tRXRα, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXRα-mediated signaling pathway in cancer cells is regulated remains elusive.. We screened a natural product library for tRXRα targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRα-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRα expression levels, demonstrating that tRXRα serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRα degradation and inhibits tRXRα-dependent AKT activity without affecting the full-length RXRα. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXRα degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRα interaction with p85α leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRα mediation. We finally show that targeting tRXRα by triptolide strongly activates TNFα death signaling and enhances the anticancer activity of other chemotherapies.. Our results identify triptolide as a new xenobiotic regulator of the tRXRα-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Caspase 8; Caspase 9; Cell Line; Cell Line, Tumor; Diterpenes; Drugs, Chinese Herbal; Enzyme Activation; Epoxy Compounds; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Phenanthrenes; Proto-Oncogene Proteins c-akt; Retinoid X Receptor alpha; Signal Transduction; Tumor Necrosis Factor-alpha

Tylophorine and many related phenanthropiperidine alkaloids are extraordinarily potent anti-proliferative agents. Despite their impressive anti-cancer activity, clinical development of these alkaloids has been hampered by their poor solubility and neurological side effects. Although it has been suggested that developing polar phenanthropiperidines will mitigate these undesired properties, the lack of practical methods for the synthesis of such analogues has limited this effort. Here, we present a concise synthetic approach to N-substituted phenanthropiperidines, which enabled a systematic investigation of structure-activity relationships at an underexplored region of the tylophorine scaffold. This work suggests that ring E of tylophorine is essential for the anti-proliferative activity of the 6,7,10,11-tetramethoxy-1,2,3,4-tetrahydrodibenzo[f,h]isoquinoline core scaffold.

Topics: Alkaloids; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Indolizines; Neoplasms; NF-kappa B; Phenanthrenes; Structure-Activity Relationship

Triptolide is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biologic properties, including anticancer properties. Among its many putative targets, this compound has been reported to bind to XPB, the largest subunit of general transcription factor TFIIH, and to cause degradation of the largest subunit Rpb1 of RNA polymerase II (RNAPII). In this study, we clarify multiple important questions concerning the significance and basis for triptolide action at this core target. Triptolide decreased Rpb1 levels in cancer cells in a manner that was correlated tightly with its cytotoxic activity. Compound exposure blocked RNAPII at promoters and decreased chromatin-bound RNAPII, both upstream and within all genes that were examined, also leading to Ser-5 hyperphosphorylation and increased ubiqutination within the Rbp1 carboxy-terminal domain. Notably, cotreatment with inhibitors of the proteasome or the cyclin-dependent kinase CDK7 inhibitors abolished the ability of triptolide to ablate Rpb1. Together, our results show that triptolide triggers a CDK7-mediated degradation of RNAPII that may offer an explanation to many of its therapeutic properties, including its robust and promising anticancer properties.

Topics: Base Sequence; Biological Products; Cell Death; Cell Line, Tumor; Chromatin Immunoprecipitation; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Diterpenes; DNA Primers; Epoxy Compounds; Humans; Neoplasms; Phenanthrenes; Phosphorylation; Proteolysis; Reverse Transcriptase Polymerase Chain Reaction; RNA Polymerase II

A series of phenanthrene imidazole with polyglycol side chain (2a-2c and 3a-3c) were synthesized and characterized by IR, NMR and MS. The cytotoxicity of 2a-2c and 3a-3c against cancer cell lines (HL-60, BGC-823, Bel-7402 and KB) in vitro were measured using MTT method. The DNA binding properties of 3a-3c were investigated by UV, fluorescence, CD spectroscopies and thermal denaturation. The results indicate that 2a exhibits higher cytotoxicity than cisplatin against BGC-823 and Bel-7402 cell lines, 3b and 3c exhibit higher cytotoxicity than 2b and 2c against BGC-823, Bel-7402 and KB cell lines. The cytotoxic effect of 2a-2c decrease with the increase of side chains length, the cytotoxic effect of 3a-3c increased with the increasing length of side chains against BGC-823, Bel-7402 and KB cell lines. Compounds 3a-3c intercalated DNA with a vertical orientation in the intercalation pocket. The binding constants of 3a-3c with Ct-DNA are 1.68×10(6), 1.51×10(6) and 0.709×10(6)M(-1), respectively. The binding affinity of 3a-3c with Ct-DNA trended to decrease with the increasing length of polyglycol side chains.

Topics: Antineoplastic Agents; Cell Line, Tumor; DNA; Glycols; Humans; Imidazoles; Intercalating Agents; Neoplasms; Phenanthrenes

To investigate the inhibitory activity of HIF-1 by triptolide and manasaantin A, two cell-based models with luciferase report gene assay were established.. Two cell-based models of HIF-1 were used to evaluate HIF-1 inhibition activity of triptolide and manasaantin A. Secreted VEGF expression induced by hypoxia was detected by ELISA with two compounds. The growth inhibition of different solid tumor cell lines was measured by the MTT assay.. The expression of firefly luciferase was induced by hypoxia in U251-HRE and T47D-HRE cells. U251-HRE model was suitable for the detection of HIF-1 inhibition activity of triptolide. The IC50 of triptolide on HIF-1 activity was (3.4 +/- 0.5) x 10(-8) mol x L(-1). The report gene assay using T47D cells co-transfected with pGL2-TK-HRE and pRL-CMV showed more sensitive inhibition activity of HIF-1 on manassantin A than that of detected by U251-HRE model. The IC50 of manassantin A on HIF-1 activity was (2.4 +/- 0.6) x 10(-8) mol x L(-1). HIF-1 target gene VEGF was also inhibited by test compounds on protein level in T47D cells. Manasaantin A showed selective inhibition on the growth of human solid cancer cell lines, especially on breast cancer and pancreatic cancer cells. Meanwhile, triplotide showed strong proliferation inhibition activity on all tested cell lines.. It is very important to select a suitable cell-based report gene assay of HIF-1 for screening of different kinds of inhibitor.

Topics: Cell Line, Tumor; Cell Proliferation; Diterpenes; Drug Evaluation, Preclinical; Epoxy Compounds; Humans; Hypoxia-Inducible Factor 1; Lignans; Luciferases; Models, Biological; Neoplasms; Phenanthrenes

Cells of most human cancers have supernumerary centrosomes. To enable an accurate chromosome segregation and cell division, these cells developed a yet unresolved molecular mechanism, clustering their extra centrosomes at two poles, thereby mimicking mitosis in normal cells. Failure of this bipolar centrosome clustering causes multipolar spindle structures and aberrant chromosomes segregation that prevent normal cell division and lead to 'mitotic catastrophe cell death'.. We used cell biology and biochemical methods, including flow cytometry, immunocytochemistry and live confocal imaging.. We identified a phenanthrene derived PARP inhibitor, known for its activity in neuroprotection under stress conditions, which exclusively eradicated multi-centrosomal human cancer cells (mammary, colon, lung, pancreas, ovarian) while acting as extra-centrosomes de-clustering agent in mitosis. Normal human proliferating cells (endothelial, epithelial and mesenchymal cells) were not impaired. Despite acting as PARP inhibitor, the cytotoxic activity of this molecule in cancer cells was not attributed to PARP inhibition alone.. We identified a water soluble phenanthridine that exclusively targets the unique dependence of most human cancer cells on their supernumerary centrosomes bi-polar clustering for their survival. This paves the way for a new selective cancer-targeting therapy, efficient in a wide range of human cancers.

Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Centrosome; Chromosome Segregation; Enzyme Inhibitors; Humans; Mitosis; Neoplasms; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Spindle Apparatus

A novel compound, acetyltanshinone IIA (ATA) was obtained from chemical modifications of tanshinone TIIA (TIIA) isolated from a medicinal plant, Salvia miltiorrhiza. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed a higher growth inhibition ability on breast cancer especially HER2 positive cells than normal cells and it inhibited xenografted tumor growth in mice. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death. ATA-mediated ROS production and its downstream apoptotic events could be blocked by an antioxidant agent, propyl gallate, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein reduced ATA-induced cell death. In conclusion, ATA is a novel anticancer agent with potent in vitro and in vivo anticancer ability. ROS-mediated Bax activation should be the mechanism by which ATA induces apoptosis and inhibits tumor growth.

Topics: Abietanes; Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Proliferation; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Doxorubicin; Female; HeLa Cells; Hep G2 Cells; HL-60 Cells; Humans; Inhibitory Concentration 50; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Neoplasms; Paclitaxel; Phenanthrenes; Propyl Gallate; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Receptor, ErbB-2; Solubility; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, little is known about its anticancer mechanism. Here, we show that CPT inhibited cancer cell proliferation by arresting cells in G(1)-G(0) phase of the cell cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation. Furthermore, we found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I- or 10% fetal bovine serum-stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel antiproliferative agent.

Topics: Antineoplastic Agents; Cell Proliferation; Cyclin D1; Down-Regulation; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Phenanthrenes; Phosphorylation; Protein Kinases; Retinoblastoma Protein; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1α.. Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1α protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1α protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1α mRNA. Unexpectedly, the HIF-1α protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1α partially prevented the cytotoxicity and apoptosis triggered by triptolide.. The potent induction of HIF-1α protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional activity, indicates the great therapeutic potential of triptolide as an anticancer drug. Meanwhile, our data further stress the possibility that HIF-1α functions in an unresolved nature or condition.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Survival; Diterpenes; Enzyme-Linked Immunosorbent Assay; Epoxy Compounds; Flow Cytometry; Fluorescent Antibody Technique; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoprecipitation; Neoplasms; Phenanthrenes; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Vascular Endothelial Growth Factors

Bay region diol epoxides are recognized ultimate carcinogens of polycyclic aromatic hydrocarbons (PAH), and in vitro studies have demonstrated that they can be detoxified by conjugation with glutathione, leading to the widely investigated hypothesis that individuals with low activity forms of glutathione-S-transferases are at higher risk of PAH induced cancer, a hypothesis that has found at most weak support in molecular epidemiology studies. A weakness in this hypothesis was that the mercapturic acids resulting from the conjugation of PAH bay region diol epoxides had never been identified in human urine. We recently analyzed smokers' urine for mercapturic acids derived from phenanthrene, the simplest PAH with a bay region. The only phenanthrene diol epoxide-derived mercapturic acid in smokers' urine was produced from the reverse diol epoxide, anti-phenanthrene-3,4-diol-1,2-epoxide (11), not the bay region diol epoxide, anti-phenanthrene-1,2-diol-3,4-epoxide (10), which does not support the hypothesis noted above. In this study, we extended these results by examining the conjugation of phenanthrene metabolites with glutathione in human hepatocytes. We identified the mercapturic acid N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c-1-phenanthryl)-L-cysteine (14a), (0.33-35.9 pmol/mL at 10 microM 8, 24 h incubation, N = 10) in all incubations with phenanthrene-3,4-diol (8) and the corresponding diol epoxide 11, but no mercapturic acids were detected in incubations with phenanthrene-1,2-diol (7), and only trace amounts were observed in incubations with the corresponding bay region diol epoxide 10. Taken together with our previous results, these studies clearly demonstrate that glutathione conjugation of a reverse diol epoxide of phenanthrene is favored over conjugation of a bay region diol epoxide. Since reverse diol epoxides of PAH are generally weakly or nonmutagenic/carcinogenic, these results, if generalizable to other PAH, do not support the widely held assumption that glutathione-S-transferases are important in the detoxification of PAH in humans.

Topics: Acetylcysteine; Adult; Aged; Aged, 80 and over; Bay-Region, Polycyclic Aromatic Hydrocarbon; Female; Glutathione; Glutathione Transferase; Hepatocytes; Humans; Male; Metabolic Detoxication, Phase II; Middle Aged; Neoplasms; Phenanthrenes; Polymorphism, Genetic

Topics: Anti-Inflammatory Agents, Non-Steroidal; bcl-2-Associated X Protein; Cell Division; Diterpenes; Epoxy Compounds; Humans; Neoplasms; Pancreatic Neoplasms; Phenanthrenes; Up-Regulation

Topics: Abietanes; Anticarcinogenic Agents; Humans; Medical Oncology; Medicine, Chinese Traditional; Neoplasm Metastasis; Neoplasms; Phenanthrenes

Two new dimeric phenanthrenes, bulbophythrins A (1) and B (2), were isolated from Bulbophyllum odoratissimum. Their structures were elucidated by HR-ESI-MS, 1D and 2DNMR spectroscopy. They were evaluated in vitro for their inhibitory ability against the growth of human leukemia cell lines K562 and HL-60, human lung adenocarcinoma A549, human hepatoma BEL-7402 and human stomach cancer SGC-7901. Both compounds showed significant cytotoxicity against the tested cell lines. Compound 1 exhibited some selectivity against HL-60 and BEL-7402 with IC(50) values of 1.27 x 10(-3) and 1.22 x 10(-3) micromol/ml respectively, whereas 2 was most active against A549 with IC(50) value of 1.18 x 10(-3) micromol/ml.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Neoplasms; Nuclear Magnetic Resonance, Biomolecular; Orchidaceae; Phenanthrenes; Plant Extracts; Spectrometry, Mass, Electrospray Ionization

Topics: ADAM Proteins; ADAM10 Protein; Amyloid Precursor Protein Secretases; Antineoplastic Agents, Alkylating; Diterpenes; Drug Discovery; Drugs, Chinese Herbal; Epoxy Compounds; Humans; Membrane Proteins; Neoplasms; Phenanthrenes

Topoisomerase II (Top2) is a ubiquitous nuclear enzyme that relieves torsional stress in chromosomal DNA during various cellular processes. Agents that target Top2, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective anticancer drugs used in the clinic. Mammalian cells possess two genetically distinct Top2 isoforms, both of which are the target of these agents. Top2alpha is essential for cell proliferation and is highly expressed in vigorously growing cells, whereas Top2beta is nonessential for growth and has recently been implicated in treatment-associated secondary malignancies, highlighting the validity of a Top2alpha-specific drug for future cancer treatment; however, no such agent has been hitherto reported. Here we show that NK314, a novel synthetic benzo[c]phenanthridine alkaloid, targets Top2alpha and not Top2beta in vivo. Unlike other Top2 inhibitors, NK314 induces Top2-DNA complexes and double-strand breaks (DSBs) in an alpha isoform-specific manner. Heterozygous disruption of the human TOP2alpha gene confers increased NK314 resistance, whereas TOP2beta homozygous knock-out cells display increased NK314 sensitivity, indicating that the alpha isoform is the cellular target. We further show that the absence of Top2beta does not alleviate NK314 hypersensitivity of cells deficient in non-homologous end-joining, a critical pathway for repairing Top2-mediated DSBs. Our results indicate that NK314 acts as a Top2alpha-specific poison in mammalian cells, with excellent potential as an efficacious and safe chemotherapeutic agent. We also suggest that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents.

Topics: Antigens, Neoplasm; Antineoplastic Agents; Cell Proliferation; DNA Breaks, Double-Stranded; DNA Topoisomerases, Type II; DNA-Binding Proteins; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Gene Deletion; HeLa Cells; Humans; Isoenzymes; Neoplasm Proteins; Neoplasms; Phenanthrenes; Poly-ADP-Ribose Binding Proteins; Topoisomerase II Inhibitors

NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that shows strong antitumor activity. It inhibited topoisomerase II activity and stabilized topoisomerase II-DNA cleavable complexes. The DNA breaks occurred within 1h after treatment with NK314 even without digestion of topoisomerase II by proteinase K, whereas etoposide required digestion of the enzyme protein in cleavable complex to detect DNA breaks. Pretreatment with topoisomerase II catalytic inhibitors, ICRF-193 and suramin, reduced both cleavable complex-mediated DNA breaks and proteinase K-independent DNA breaks, but protease inhibitors and nuclease inhibitors only decreased the latter. These results indicate that NK314 might affect topoisomerase II in the different manner from cleavable complex formation and activate intracellular proteinase and nuclease to produce DNA fragmentation. As a result of this unique mechanism of DNA breakage, NK314 showed substantial growth inhibition of topoisomerase II inhibitor-resistant tumors.

Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cell Proliferation; DNA Breaks, Double-Stranded; DNA Topoisomerases, Type II; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Endopeptidase K; Enzyme Inhibitors; Female; HL-60 Cells; Humans; Leukemia P388; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Phenanthrenes; Time Factors; Topoisomerase II Inhibitors; Xenograft Model Antitumor Assays

Many studies have investigated the effects of glutathione S-transferase (GST) polymorphisms on cancer incidence in people exposed to carcinogenic polycyclic aromatic hydrocarbons (PAHs). The basis for this is that the carcinogenic bay region diol epoxide metabolites of several PAH are detoxified by GSTs in in vitro studies. However, there are no reports in the literature on the identification in urine of the mercapturic acid metabolites that would result from this process in humans. We addressed this by developing a method for quantitation in human urine of mercapturic acids which would be formed from angular ring diol epoxides of phenanthrene (Phe), the simplest PAH with a bay region, and a common environmental pollutant. We prepared standard mercapturic acids by reactions of syn- or anti-Phe-1,2-diol-3,4-epoxide and syn- or anti-Phe-3,4-diol-1,2-epoxide with N-acetylcysteine. Analysis of human urine conclusively demonstrated that the only detectable mercapturic acid of this type--N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c/t-1-phenanthryl)-L-cysteine (anti-PheDE-1-NAC)--was derived from the 'reverse diol epoxide', anti-Phe-3,4-diol-1,2-epoxide, and not from the bay region diol epoxides, syn- or anti-Phe-1,2-diol-3,4-epoxide. Levels of anti-PheDE-1-NAC in the urine of 36 smokers were (mean +/- SD) 728 +/- 859 fmol/ml urine. The results of this study provide the first evidence for a mercapturic acid of a PAH diol epoxide in human urine, but it was not derived from a bay region diol epoxide as molecular epidemiologic studies have presumed, but rather from a reverse diol epoxide, representative of metabolites with little if any carcinogenic activity. These results demonstrate the need for integration of genotyping and phenotyping information in molecular epidemiology studies.

Topics: Acetylcysteine; Biotransformation; Carcinogens; Chromatography, High Pressure Liquid; Glutathione Transferase; Humans; Inactivation, Metabolic; Models, Molecular; Neoplasms; Phenanthrenes; Polymorphism, Genetic; Spectrometry, Mass, Electrospray Ionization

Remarkably different conformations can result when DNA binds with stereoisomeric compounds containing differing absolute configurations of substituents about chiral carbon atoms. Furthermore, the biochemical functions of covalent adducts with DNA are strongly affected by the stereochemistry of the ligands. Such stereochemical effects are manifested by DNA covalent adducts derived from metabolites of the non-planar fjord region environmental chemical carcinogen benzo[c]phenanthrene. To analyze these phenomena, an extensive conformational investigation for R and S stereoisomeric adducts to deoxyadenosine, derived from trans addition of enantiomeric anti diol epoxide metabolites of benzo[c]phenanthrene, has been carried out. We have surveyed the potential energy surface of the two adducts by varying systematically at 5 degree intervals in combination, the three important torsion angles that govern conformational flexibility of the carcinogen bulk with respect to the linked nucleoside. We carried out a grid search by creating 373, 248 structures for each isomer, and evaluated their molecular mechanical energies. This has permitted us to map the potential energy surface of each adduct in these three variables, and to delineate their low energy regions. The maps have a symmetric relationship which stems from the near mirror-image stereochemistry in the R and S isomers. This produces near mirror-image low energy structures in the nucleoside adducts. The limited sets of stereoisomer-dependent conformational domains delineated are determined by steric effects. Moreover, these features have been experimentally demonstrated to play governing structural roles in such carcinogen-damaged DNA duplexes: opposite orientations in the stereoisomer pairs computed for the nucleosides are observed by high-resolution NMR in the similarly modified DNA double helices, and are likely to play important roles in their interactions with enzymes involved in DNA transactions, and hence their biological activities.

Topics: Carcinogens; Deoxyadenosines; DNA; DNA Adducts; DNA Damage; Hydrocarbons; Magnetic Resonance Spectroscopy; Models, Statistical; Molecular Conformation; Neoplasms; Nucleic Acid Conformation; Phenanthrenes; Stereoisomerism; Thermodynamics

Triptolide (PG490), a diterpene triepoxide, is a potent immunosuppressive agent extracted from the Chinese herb Tripterygium wilfordii. We have previously shown that triptolide blocks NF-kappaB activation and sensitizes tumor necrosis factor (TNF-alpha)-resistant tumor cell lines to TNF-alpha-induced apoptosis. We show here that triptolide enhances chemotherapy-induced apoptosis. In triptolide-treated cells, the expression of p53 increased but the transcriptional function of p53 was inhibited, and we observed a down-regulation of p21(waf1/cip1), a p53-responsive gene. The increase in levels of the p53 protein was mediated by enhanced translation of the p53 protein. Additionally, triptolide induced accumulation of cells in S phase and blocked doxorubicin-mediated accumulation of cells in G(2)/M and doxorubicin-mediated induction of p21. Our data suggest that triptolide, by blocking p21-mediated growth arrest, enhances apoptosis in tumor cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Base Sequence; Cell Cycle; Diterpenes; DNA Primers; DNA, Neoplasm; Doxorubicin; Drug Synergism; Epoxy Compounds; Humans; Mice; Neoplasms; Oncogene Protein p21(ras); Phenanthrenes; Protein Binding; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Progress in the treatment of solid tumors has been slow and sporadic. The efficacy of conventional chemotherapy in solid tumors is limited because tumors frequently have mutations in the p53 gene. Also, chemotherapy only kills rapidly dividing cells. Members of the tumor necrosis factor (TNF) family, however, induce apoptosis regardless of the p53 phenotype. Unfortunately, the cytotoxicity of TNF-alpha is limited by its activation of NF-kappaB and activation of NF-kappaB is proinflammatory. We have identified a compound called PG490, that is composed of purified triptolide, which induces apoptosis in tumor cells and sensitizes tumor cells to TNF-alpha-induced apoptosis. PG490 potently inhibited TNF-alpha-induced activation of NF-kappaB. PG490 also blocked TNF-alpha-mediated induction of c-IAP2 (hiap-1) and c-IAP1 (hiap-2), members of the inhibitor of apoptosis (IAP) family. Interestingly, PG490 did not block DNA binding of NF-kappaB, but it blocked transactivation of NF-kappaB. Our identification of a compound that blocks TNF-alpha-induced activation of NF-kappaB may enhance the cytotoxicity of TNF-alpha on tumors in vivo and limit its proinflammatory effects.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Base Sequence; Diterpenes; DNA Primers; Drug Synergism; Epoxy Compounds; Humans; Inhibitor of Apoptosis Proteins; Neoplasms; NF-kappa B; Phenanthrenes; Protein Biosynthesis; Proteins; Transcriptional Activation; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m2 were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m2 and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and alpha-slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t1/2 of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m2 and 18.3 liters/h/m2, respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m2.

Topics: Adult; Aged; Antineoplastic Agents; Arrhythmias, Cardiac; Blood Pressure; Chrysenes; Digestive System; Drug Administration Schedule; Drug Evaluation; Electroencephalography; Female; Humans; Male; Middle Aged; Neoplasms; Nervous System; Phenanthrenes; Propylene Glycols

Aromatic amines are urinary bladder carcinogens in man and induce tumors at a number of sites in experimental animals including the liver, mammary gland, intestine, and bladder. In this review, the particular pathways involved in the metabolic activation of aromatic amines are considered as well as the specific DNA adducts formed in target and nontarget tissue. Particular emphasis is placed on the following compounds: 1-naphthylamine, 2-naphthylamine, 4-aminobiphenyl, 4-acetylaminobiphenyl, 4-acetylamino-4'-fluorobiphenyl, 3,2'-dimethyl-4-aminobiphenyl, 2-acetylaminofluorene, benzidine, N-methyl-4-aminoazobenzene, 4-aminoazobenzene, and 2-acetylaminophenanthrene.

Topics: 1-Naphthylamine; 2-Acetylaminofluorene; 2-Naphthylamine; Amines; Aminobiphenyl Compounds; Animals; Benzene Derivatives; Benzidines; Biotransformation; Carcinogens; DNA; Humans; Neoplasms; Phenanthrenes; Structure-Activity Relationship

Topics: Animals; Aristolochic Acids; Consumer Product Safety; Germany, West; Legislation as Topic; Neoplasms; Phenanthrenes; Rats; Rats, Inbred Strains

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.

Topics: Antineoplastic Agents, Phytogenic; Drug Evaluation; Glaucarubin; Half-Life; Humans; Hypotension; Infusions, Parenteral; Liver; Neoplasms; Phenanthrenes; Quassins; Radioimmunoassay

This contribution is concerned with the concept of immunotherapy and the search for the new therapeutic agents. Examples given are, aristolochic acid, Poly I:C and Interferon. The results show a clear correlation of in vivo and in vitro activity of Interferon in the case of virus infections (eccema vaccinatum). No certainty could be determined concerning the efficiency of A.S. and Poly I:C, determined concerning the efficiency of A.S. and Poly I:C, if an Interferon-mechanism was anticipated.

Topics: Aristolochic Acids; Dioxolanes; Humans; Inflammation; Interferons; Leukemia; Neoplasms; Phenanthrenes; Poly I-C; Rosette Formation; Virus Diseases

Many of the polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene (B[a]P), benzanthracene (BA), 3-methylcholanthrene (3-MC)) are not only carcinogenic, but also induce AHH in human tissues. Recently, chrysene has been implicated as an etiologic determinant of chemical carcinogenesis. Here we describe the ability of chrysene to induce AHH in cultured human lymphocytes. Lymphocytes were obtained from 9 healthy subjects, divided into 2 sets, and cultured in duplicate, triplicate, or quadruplicate for 48 h. Chrysene (25 microM final concentration) in acetone was then added to the induced culture set and the control set received acetone alone. Lymphocytes were then cultured an additional 24 h before harvesting. AHH was quantitated by a fluorometric analysis of the phenolic metabolites produced by incubating the lymphocytes with B[a]P for 35 min. A significant increase in enzyme induction occurred in the chrysene-induced cultures compared with control (non-induced) cells (one-tailed student t-test; P less than 0.001). It was also observed that the interindividual variation in AHH inducibility seen with other PAHs is also observed with chrysene.

Topics: Aryl Hydrocarbon Hydroxylases; Carcinogens; Chrysenes; Enzyme Induction; Humans; In Vitro Techniques; Lymphocytes; Neoplasms; Phenanthrenes

1. In several experiments on groups of mice aristolochic acid administered by mouth reduced the induction rate of methyl-cholanthrene tumours. 2. In cases where such tumours were influenced their growth was slowed down. 3. If aristolochic acid treatment is started a long time after the methylcholanthrene injection its effect on carcinogenesis is weaker. 4. Oral administration gave better results than injection. 5. Pertussis vaccine seems to have no significant influence on tumour development.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Antineoplastic Agents; Dioxolanes; Methylcholanthrene; Mice; Neoplasms; Pertussis Vaccine; Phagocytosis; Phenanthrenes; Plant Extracts

Topics: Adult; Anthracenes; Benz(a)Anthracenes; Benzopyrenes; Chromatography; Humans; Hydrocarbons; Male; Neoplasms; Phenanthrenes; Smoking; Spectrum Analysis; Tars

Topics: Animals; Antineoplastic Agents; Benz(a)Anthracenes; Benzopyrenes; Carcinogenesis; Carcinogens; Glycols; Hydrocarbons; Methylcholanthrene; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Phenanthrenes; Research; Sarcoma; Sarcoma, Experimental

Topics: Antineoplastic Agents; Aristolochic Acids; Child; Drug Therapy; Neoplasms; Phenanthrenes; Research; Toxicology

Topics: Animals; Animals, Newborn; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Carcinoma, Hepatocellular; Liver Neoplasms; Lung Neoplasms; Lymphoma; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mice; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Research; Toxicology

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Hydroquinones; Mice; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Phenols; Rats; Research; Sarcoma, Experimental

Topics: Ascites; Benzoquinones; Neoplasms; Neoplasms, Experimental; Oxidation-Reduction; Phenanthrenes

Topics: Animals; Humans; Neoplasms; Phenanthrenes; Sarcoma, Experimental

Topics: Breast Neoplasms; Humans; Molecular Structure; Neoplasms; Phenanthrenes; Steroids

Topics: 2-Acetylaminofluorene; Animals; Benz(a)Anthracenes; Carcinogens; Chrysenes; Fluorenes; Gonadal Steroid Hormones; Methylcholanthrene; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Rats; Sex Characteristics

Topics: Humans; Neoplasms; Phenanthrenes