gambogic-acid and Neoplasms

The United States Food and Drug Administration has permitted number of therapeutic agents for cancer treatment. Most of them are expensive and have some degree of systemic toxicity which makes overbearing in clinical settings. Although advanced research continuously applied in cancer therapeutics, but drug resistance, metastasis, and recurrence remain unanswerable. These accounts to an urgent clinical need to discover natural compounds with precisely safe and highly efficient for the cancer prevention and cancer therapy. Gambogic acid (GA) is the principle bioactive and caged xanthone component, a brownish gamboge resin secreted from the of Garcinia hanburyi tree. This molecule showed a spectrum of biological and clinical benefits against various cancers. In this review, we document distinct biological characteristics of GA as a novel anti-cancer agent. This review also delineates specific molecular mechanism(s) of GA that are involved in anti-cancer, anti-metastasis, anti-angiogenesis, and chemo-/radiation sensitizer activities. Furthermore, recent evidence, development, and implementation of various nanoformulations of gambogic acid (nanomedicine) have been described.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chemoradiotherapy; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Drug Carriers; Drug Costs; Garcinia; Humans; Nanomedicine; Nanoparticles; Neoplasms; Radiation-Sensitizing Agents; Resins, Plant; Treatment Outcome; Xanthones; Xenograft Model Antitumor Assays

Gambogic acid (GA), a kind of dry resin secreted by the

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Drug Delivery Systems; Drug Resistance, Neoplasm; Garcinia; Humans; Micelles; Nanostructures; Neoplasms; Neovascularization, Pathologic; Xanthones

Anticancer agents are critical for the cancer treatment, but side effects and the drug resistance associated with the currently used anticancer agents create an urgent need to explore novel drugs with low side effects and high efficacy. 1,2,3-Triazole is privileged building block in the discovery of new anticancer agents, and some of its derivatives have already been applied in clinics or under clinical trials for fighting against cancers. Hybrid molecules occupy an important position in cancer control, and hybridization of 1,2,3-triazole framework with other anticancer pharmacophores may provide valuable therapeutic intervention for the treatment of cancer, especially drug-resistant cancer. This review emphasizes the recent advances in 1,2,3-triazole-containing hybrids with anticancer potential, covering articles published between 2015 and 2019, and the structure-activity relationships, together with mechanisms of action are also discussed.

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

Natural compounds have enormous biological and clinical activity against dreadful diseases such as cancer, as well as cardiovascular and neurodegenerative disorders. In spite of the widespread research carried out in the field of cancer therapeutics, cancer is one of the most prevalent diseases with no perfect treatment till date. Adverse side effects and the development of chemoresistance are the imperative limiting factors associated with conventional chemotherapeutics. For this reason, there is an urgent need to find compounds that are highly safe and efficacious for the prevention and treatment of cancer. Gambogic acid (GA) is a xanthone structure extracted from the dry, brownish gamboge resin secreted from the Garcinia hanburyi tree in Southeast Asia and has inherent anti-cancer properties. In this review, the molecular mechanisms underlying the targets of GA that are liable for its effective anti-cancer activity are discussed that reveal the potential of GA as a pertinent candidate that can be appropriately developed and designed into a capable anti-cancer drug.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Garcinia; Humans; Models, Biological; Molecular Structure; Neoplasms; Xanthones

Natural compounds have been known as biosafety agents for their significant clinical and biological activity against dreadful diseases, including cancer, cardiovascular, and neurodegenerative disorders. Gambogic acid (GA), a naturally occurring xanthone-based moiety, reported from Garcinia hanburyi tree, is known to perform numerous intracellular and extracellular actions, including programmed cell death, autophagy, cell cycle arrest, antiangiogenesis, antimetastatic, and anti-inflammatory activities. In addition, GA-based synergistic approaches have been proven to enhance the healing strength of existing chemotherapeutic agents along with lesser side effects. The present review uncovers the bio-therapeutic potential of gambogic acid along with the possible mechanistic interactions of GA with its recognized cellular targets.

Topics: Animals; Apoptosis; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction; Xanthones

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Prenylated caged xanthones are "privileged structure" characterized by the presence of the unusual 4-oxo-tricyclo[4.3.1.0(3,7)]dec-8-en-2-one scaffold. The natural sources of these compounds confines mainly in the Garcinia genus in the family of Guttiferae. Gambogic acid is the most abundant substance and most of the studies have been done on this compound, particularly as a new potential antitumor agent. The history, sources, structural diversity, and biological activities of these compounds are covered.. This review is written with the intention to provide additional aspects from what have been published of prenylated caged xanthones, including history, sources, structural diversity, and biological activities.. This review has been compiled using information from a number of reliable references mainly from major databases including SciFinder, ScienceDirect, and PubMed.. More than 120 prenylated caged xanthones have been found in the plant genera Garcinia, Cratoxylum, and Dascymaschalon. These compounds exhibited various potentially useful biological activities such as anticancer, anti-HIV-1, antibacterial, anti-inflammatory, and neurotrophic activities.. Prenylated caged xanthones, both naturally occurring and synthetic analogues, have been identified as promising bioactive compounds, especially for anticancer agents. Gambogic acid has been demonstrated to be a highly valuable lead compound for antitumor chemotherapy. The structure activity relationship (SAR) study of its analogues is still the subject of intensive research. Apoptosis cytotoxic mechanism has been identified as the major pathway. Research on the delineation of the in-depth mechanism of action is still on-going. Analogues of gambogic acid had been identified to be effective against a rare and special form of liver cancer, cholangiocarcinoma for which currently there is no chemotherapeutic treatment available.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Humans; Neoplasms; Plant Extracts; Prenylation; Structure-Activity Relationship; Xanthones

Gambogic acid (GA) is a caged xanthone that is derived from Garcinia hanburyi and functions as a strong apoptotic inducer in many types of cancer cells. The distinct effectiveness of GA has led to its characterization as a novel anti-cancer agent. There is an increasing number of research studies focused on elucidating the molecular mechanisms of GA-induced anti-cancer effects, and several critical signaling pathways have been reported to be influenced by GA treatment. In this review, we summarize the multiple functional effects of GA administration in cancer cells including the induction of apoptosis, the inhibition of proliferation and the prevention of cancer metastasis and tumor angiogenesis.

Topics: Antineoplastic Agents, Phytogenic; Biological Products; Cell Proliferation; Garcinia; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Xanthones

Gambogic acid is a pure active compound isolated from the traditional Chinese medicinal plant gamboge (Garcinia morella Desv.). Based on the preliminary results of a phase I study, this phase IIa study compared the efficacy and safety of different dosage schedules of gambogic acid in patients with advanced malignant tumors.. Patients with advanced or metastases cancer who had not received any effective routine conventional treatment or who had failed to respond to the existing conventional treatment were randomly assigned to receive either 45 mg/m(2) gambogic acid intravenously from Days 1 to 5 of a 2-week cycle (Group A), or 45 mg/m(2) every other day for a total of five times during a 2-week cycle (Group B). The primary endpoint was objective response rate (ORR).. Twenty-one patients assigned to Group A and 26 to Group B were included in the final analysis. The ORRs were 14.3% in Group A and 0% in Group B. It was not possible to analyze the significant difference because one of the values was zero. The disease control rates (DCRs) were 76.2% in Group A and 61.5% in Group B (P = 0.0456). The observed adverse reactions were mostly Grades I and II, and occurred in most patients after administration of the trial drug. There was no significant difference in the incidence of adverse reactions between the two arms.. The preliminary results of this phase IIa exploratory study suggest that gambogic acid has a favorable safety profile when administered at 45 mg/m(2). The DCR was greater in patients receiving gambogic acid on Days 1 - 5 of a 2-week cycle, but the incidence of adverse reactions was similar irrespective of the administration schedule.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Female; Humans; Injections; Male; Middle Aged; Neoplasms; Xanthones

Recent studies have shown that traditional Chinese medicine (TCM), such as gambogic acid (GA), is involved in the regulation of tumor immune microenvironment and can be combined with other anti-tumor treatment strategies. Here, we used GA as an adjuvant to construct a nano-vaccine to improve the anti-tumor immune response of colorectal cancer (CRC).. We used a previously reported two-step emulsification method to obtain poly (lactic-co-glycolic acid) /GA nanoparticles (PLGA/GA NPs), and then CT26 colon cancer cell membrane (CCM) was used to obtain CCM-PLGA/GA NPs. This novel nano-vaccine, CCM-PLGA/GA NPs, was co-synthesized with GA as an adjuvant and neoantigen provided by CT26 CCM. We further confirmed the stability, tumor targeting, and cytotoxicity of CCM-PLGA/GA NPs. The regulatory effect on the tumor immune microenvironment, the anti-tumor efficacy, and the combined anti-tumor efficacy with anti-PD-1 monoclonal Antibodies (mAbs) of this novel nano-vaccine was also detected in vivo.. We successfully constructed the CCM-PLGA/GA NPs. In vitro and in vivo tests showed low biological toxicity, as well as the high tumor-targeting ability of the CCM-PLGA/GA NPs. Besides, we revealed a remarkable effect of CCM-PLGA/GA NPs to activate the maturation of dendritic cells (DCs) and the formation of a positive anti-tumor immune microenvironment.. This novel nano-vaccine constructed with GA as the adjuvant and CCM providing the tumor antigen can not only directly kill tumors by enhancing the ability of GA to target tumors, but also indirectly kill tumors by regulating tumor immune microenvironment, providing a new strategy for immunotherapy of CRC.

Topics: Adjuvants, Immunologic; Cell Membrane; Cytoplasm; Dendritic Cells; Nanoparticles; Neoplasms

GPCRs are the most potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based anti-cancer drug is not fully investigated. Herein, we identified GPR108, a GPCR protein described in innate immune system, is a potential therapeutic target of cancer. Depletion of GPR108 dramatically inhibited the survival of various cancers. Notably, TNFα activation of NF-κB was totally impaired after GPR108 knockout. We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. Importantly, GA engaged with GPR108 and promoted its degradation, knockout of GPR108 remarkably blocked GA inhibition of NF-κB signaling. Furthermore, in vitro and in vivo assays demonstrated that GA was dependent on GPR108 to exert anti-cancer activity. Overall, our findings supported GPR108 as a promising therapeutic target of cancer, and provided a small molecule inhibitor GA directly and selectively targeting GPR108 for cancer therapy.

Topics: Cell Line, Tumor; Humans; Neoplasms; NF-kappa B; Receptors, G-Protein-Coupled; Signal Transduction; Xanthones

Whether or not the anticancer activity of gambogic acid is achieved

Topics: Neoplasms; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Xanthones

Inspired by the critical role of nanocarrier in biomaterials modification, we synthesized a mesoporous rod-structure hydroxyapatite (MR-HAp) nanoparticles for boosting gambogic acid (GA) bioavailability in cells and improving the tumor therapy. As expected, the GA loading ratio of MR-HAp was up to about 96.97% and GA-loaded MR-HAp (MR-HAp/GA) demonstrates a sustained release performance. Furthermore, a substantial improvement was observed in inhibiting the cell proliferation and inducing the apoptosis of HeLa cells, as the cell viability was decreased to 89.6% and the apoptosis was increased to 49.2% when the cells treated with MR-HAp/GA at a GA concentration of 1 μg/mL for 72 h. The remarkable inhibition effect of cell proliferation and the enhanced inducing apoptosis are attributed to the increasing intracellular reactive oxygen species level and reduced mitochondrial membrane potential. This result provides a promising and facile approach for highly efficient tumor treatment.

Topics: Cell Line, Tumor; Durapatite; HeLa Cells; Humans; Neoplasms; Xanthones

An active-passive dual-targeting gambogic acid HPMA Copolymer Coupling drug system with high efficiency, low toxicity and high selectivity was constructed.. The gambogic acid HPMA copolymer coupling drug system was constructed and its structure was characterized. The cytotoxicity of gambogic acid HPMA copolymer was detected by MTT assay. The pharmacokinetics of gambogic acid HPMA copolymer was evaluated in mice. Targetability of gambogic acid HPMA copolymer was evaluated by tissue distribution experiment. The in vitro antitumor activity of gambogic acid HPMA copolymer was evaluated by pharmacodynamics experiment in mice.. Two copolymers of gambogic acid HPMA were successfully prepared. The copolymers showed reduced cytotoxicity and a certain sustained release effect and targeting property. In vivo pharmacodynamic experiments also showed better anti-tumor effects than GA.. In this study, gambogic acid was combined with HPMA polymer and the targeting molecule D-galactose/folic acid to form a polymer micelle with high efficiency, low toxicity and high selectivity for active-passive dual targeting. The construction of the drug system provides new ideas for future formulation research and development.

Topics: Animals; Cell Line, Tumor; Methacrylates; Mice; Neoplasms; Polymers; Xanthones

Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors.. A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo.. The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model.. Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy.

Topics: Animals; Cell Line, Tumor; Drug Carriers; Drug Liberation; HSP90 Heat-Shock Proteins; Humans; Lasers; Male; Mice; Mice, Inbred BALB C; Nanostructures; Neoplasms; Photosensitizing Agents; Photothermal Therapy; Rats; Rats, Sprague-Dawley; Tissue Distribution; Transplantation, Heterologous; Xanthones

Reactive oxygen species (ROS) play an important role in cellular metabolism and many oxidative stress related diseases. Oxidative stress results from toxic effects of ROS and plays a critical role in the pathogenesis of a variety of diseases like cancers and many important biological processes. It is known that the unique feature of high intracellular ROS level in cancer cells can be considered as target and utilized as a useful cancer-related stimulus to mediate intracellular drug delivery. Therefore, biomaterials responsive to excess level of ROS are of great importance in biomedical applications. In this study, a novel ROS-responsive polymer based on L-methionine poly(ester amide) (Met-PEA-PEG) was designed, synthesized, characterized and self-assembled into nano-micellar-type nanoparticles (NP). The Met-PEA-PEG NP exhibited responsiveness to an oxidative environment. The size and morphology of the nanoparticle changed rapidly in the presence of H

Topics: Antineoplastic Agents; Delayed-Action Preparations; Drug Delivery Systems; HeLa Cells; Humans; Methionine; Nanoparticles; Neoplasms; PC-3 Cells; Polyesters; Reactive Oxygen Species; Xanthones

A novel multiple environment-sensitive polymeric prodrug of gambogic acid (GA) based on chitosan graftomer was fabricated for cancer treatment. Folic acid-chitosan conjugates was complexed with thermosensitive amine terminated poly-N-isopropylacrylamide (NH

Topics: Acrylic Resins; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chitosan; Drug Carriers; Drug Liberation; Folic Acid; Humans; Hydrogen-Ion Concentration; Male; Mice; Micelles; Neoplasms; Prodrugs; Temperature; Xanthones

The surface potential of particles is a double-edged sword for nanomedicine. The negative charge can protect nanoparticles from clearance before they reach the tumor tissue; however, it is difficult to phagocytose the negative particles by target cells due to the negative potential of the cytomembrane. Preparing techniques to efficiently release the encapsulated drug from negative nanoparticles into target cells is a formidable challenge facing advanced drug delivery studies. Herein, we have developed a novel "mosaic-type" nanoparticle system (GA-Cy7-NP) for selective drug release targeting hypoxic cancer cells. In this system, hypoxia-targeting near-infrared dye (Cy7) moiety with a positive charge is conjugated to an antitumor agent, namely, gambogic acid (GA). This conjugate could self-assemble into nanoparticles with surfactin in an aqueous solution, where the Cy7 group is embedded in the negatively charged particle surface formed by surfactin. Most remarkably, the "mosaic-type" nanoparticles could selectively release the loaded drug conjugates into hypoxic cancer cells without particle internalization. Using in vitro PC3 cell and xenograft mouse models, we demonstrate that GA-Cy7-NP exhibits enhanced drug distribution in tumor cells and superior antitumor activity as compared to the prototype drug when evaluated in terms of cell proliferation, tumor growth, and angiogenesis assay.

Topics: Animals; Antineoplastic Agents; Carbocyanines; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Drug Liberation; Humans; Lipopeptides; Male; Mice; Mice, Nude; Nanoparticles; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Particle Size; Peptides, Cyclic; Xanthones

A ternary core/shell based nanoparticulate complex was designed for the sequential and site-specific drug delivery. First, bovine serum albumin nanoparticles (BSA NPs) were served as the core for loading gambogic acid (GA). Subsequently, the BSA NPs were adsorbed by polyethylenimine and then shielded with carboxymethyl chitosan-folate (CMCS-FA) as the outer shell for encapsulating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), forming the GA/TRAIL co-delivery BSA (GTB) NPs. In normal tissues, the GTB NPs were negatively charged; in acidic tumor tissues, the shielding CMCS-FA was detached, allowing the release of TRAIL, which binds to the cell death receptor on the plasma membrane. The resulting positively charged complex promoted cellular internalization and escaped from lysosomes, producing a rapid release of GA, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. In vitro and in vivo studies confirmed that GTB NPs could enhance antitumor efficacy and reduce adverse effects.

Topics: A549 Cells; Animals; Antineoplastic Agents; Cell Survival; Chitosan; Drug Delivery Systems; Drug Liberation; Folic Acid; Humans; Male; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Polyethyleneimine; Serum Albumin, Bovine; TNF-Related Apoptosis-Inducing Ligand; Tumor Burden; Xanthones

β-Cyclodextrin can form inclusion complex with a series of guest molecules including phenyl moieties, and has gained considerable popularity in the study of supramolecular nanostructure. In this study, a biodegradable nanocomplex (HA(CD)-4Phe4 nanocomplex) was developed from β-cyclodextrin grafted hyaluronic acid (HA) and phenylalanine based poly(ester amide). The phenylalanine based poly(ester amide) is a biodegradable pseudo protein which provides the encapsulation capacity for gambogic acid (GA), a naturally-derived chemotherapeutic which has been effectively employed to treat multidrug resistant tumor. The therapeutic potency of free GA is limited due to its poor solubility in water and the lack of tumor-selective toxicity. The nanocomplex carrier enhanced the solubility and availability of GA in aqueous media, and the HA component enabled the targeted delivery to tumor cells with overexpression of CD44 receptors. In the presence of hyaluronidase, the release of GA from the nanocomplex was significantly accelerated, due to the enzymatic biodegradation of the carrier. Compared to free GA, GA-loaded nanocomplex exhibited improved cytotoxicity in MDA-MB-435/MDR multidrug resistant melanoma cells, and induced enhanced level of apoptosis and mitochondrial depolarization, at low concentration of GA (1-2µM). The nanocomplex enhanced the therapeutic potency of GA, especially when diluted in physiological environment. In addition, suppressed matrix metalloproteinase activity was also detected in MDA-MB-435/MDR cells treated by GA-loaded nanocomplex, which demonstrated its potency in the inhibition of tumor metastasis. The in vitro data suggested that HA(CD)-4Phe4 nanocomplex could provide a promising alternative in the treatment of multidrug resistant tumor cells.. Gambogic acid (GA), naturally derived from genus Garcinia trees, exhibited significant cytotoxic activity against multiple types of tumors with resistance to traditional chemotherapeutics. Unfortunately, the poor solubility of GA in conventional pharmaceutical solvents and non-targeted distribution in normal tissues greatly limited its therapeutic potency. To overcome the challenges, we develop a nanoplatform from the supramolecular assembly of β-cyclodextrin grafted hyaluronic acid (HA) and phenylalanine based pseudo protein. The pseudo protein in the nanocomplex provided the hydrophobic interaction and loading capacity for GA, while the HA component targeted the overexpressed CD44 receptor and improved the selective endocytosis in multidrug resistant melanoma cells. The supramolecular nanocomplex provide a promising platform for the delivery of hydrophobic chemotherapeutics to improve the bioavailability and efficiency.

Topics: Cell Line, Tumor; Cyclodextrins; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Hyaluronic Acid; Nanostructures; Neoplasms; Xanthones

Gambogic acid (GA) exhibits a broad spectrum of anticancer activity and low chemotoxicity to normal tissues. However, poor aqueous solubility and sensitivity to hydrolysis make its pharmaceutical applications a challenge. Linear and branched Arg-based poly(ester urea urethane)s (Arg-PEUUs), folate (FA)-conjugated Arg PEUUs (FA-Arg-PEUUs), and their self-assembled nanoparticles (NPs) were designed, synthesized, and studied as the potential GA carriers for cancer treatment. The average diameters of linear or branched Arg-PEUU/FA-Arg-PEUU NPs were 98-267 nm. FA-Arg-PEUU NPs adhered onto and were internalized into HeLa and A549 cells, and showed no cytotoxicity. The GA loading efficiency in the NP carriers ranged from 40 to 98%, depending on the feed weight ratio of GA to Arg-PEUU and the Arg-PEUU polymer structure (i.e., linear vs. branched). The GA at 2 µg/mL concentration delivered by the FA-Arg-PEUU NP carriers had higher cytotoxicity and induced a higher apoptosis percentage against folate receptor (FR)-overexpressed HeLa or HCT116 than Arg-PEUU NPs. When compared to the free GA treatment, the GA loaded in the FA-Arg-PEUU NP carriers also led to significant loss of the mitochondrial membrane potential in a higher percentage of the cancer cell population and more DNA fragmentation. The GA loaded in FA-Arg-PEUU NP carriers at as low as 0.6 µg/mL GA concentration led to lower MMP-2 and MMP-9 activity of cancer cells compared to free GA, suggesting that GA-loaded Arg-PEUU NPs may have greater potential to reduce cancer cell invasion and metastasis than free GA. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 475-490, 2017.

Topics: A549 Cells; Drug Carriers; Folic Acid; HeLa Cells; Humans; Nanoparticles; Neoplasms; Polyesters; Xanthones

Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure-activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Garcinia; HSP90 Heat-Shock Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Structure-Activity Relationship; Xanthones

The limited translational value in clinic of analyses performed on 2-D cell cultures has prompted a shift toward the generation of 3-dimensional (3-D) multicellular systems. Here we present a spontaneously-forming in vitro cancer spheroid model, referred to as spheroids(MARY-X), that precisely reflects the pathophysiological features commonly found in tumor tissues and the lymphovascular embolus. In addition, we have developed a rapid, inexpensive means to evaluate response following drug treatment where spheroid dissolution indices from brightfield image analyses are used to construct dose-response curves resulting in relevant IC50 values. Using the spheroids(MARY-X) model, we demonstrate the unique ability of a new class of molecules, containing the caged Garcinia xanthone (CGX) motif, to induce spheroidal dissolution and apoptosis at IC50 values of 0.42 +/-0.02 μM for gambogic acid and 0.66 +/-0.02 μM for MAD28. On the other hand, treatment of spheroids(MARY-X) with various currently approved chemotherapeutics of solid and blood-borne cancer types failed to induce any response as indicated by high dissolution indices and subsequent poor IC50 values, such as 7.8 +/-3.1 μM for paclitaxel. Our studies highlight the significance of the spheroids(MARY-X) model in drug screening and underscore the potential of the CGX motif as a promising anticancer pharmacophore.

Topics: Amino Acid Motifs; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Garcinia; Humans; Immunohistochemistry; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Microscopy, Confocal; Microscopy, Fluorescence; Neoplasm Transplantation; Neoplasms; Spheroids, Cellular; Tumor Cells, Cultured; Xanthones

Topics: Antineoplastic Agents; Cell Growth Processes; Cell Line, Tumor; Humans; Neoplasms; Xanthones

Our previous studies revealed that gambogic acid (GA), the major active ingredient of gamboge, possessed antiangiogenic activities. In this study, we further explored the mechanism of inhibition effects of GA in tumor angiogenesis. The results of luciferase, RT-PCR, and ELISA assays indicated that GA significantly decreased transcription activation, mRNA expression, and secretion of VEGF in hypoxia. We detected that GA had no effect on mRNA level of HIF-1α which targets VEGF gene, but the increase of HIF-1α protein expression in hypoxia was repressed by GA, which can be reversed by proteasomal inhibitor MG132 and siRNA of VHL. But GA exhibited no effect on expression of VHL both in normoxia and hypoxia. HIF prolyl hydroxylases (PHD enzymes) act as oxygen sensors regulating HIF, and hence angiogenesis. Our results showed that GA potentially enhanced level of PHD2, the most important HIF hydroxylase, and showed no effect on PHD1 and PHD3. Transient transfection of siRNA of PHD2 could eliminate GA-induced VEGF secretion increase. Growth of HepG2 xenografts in BALB/cA nude mice was inhibited by GA and angiogenesis was repressed significantly in tumor xenografts by immunohistochemical staining of CD-31, a vascular endothelial marker, accompanied with decrease of HIF-1α and increase of PHD2 expression in tissue extracts. This work provides the demonstration that GA shows anti-angiogenic effects via inhibiting PHD2-VHL-HIF-1α pathway.

Topics: Angiogenesis Inhibitors; Animals; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neovascularization, Pathologic; RNA, Messenger; Tumor Burden; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein; Xanthones; Xenograft Model Antitumor Assays

The natural product gambogic acid exhibits high potency in inhibiting cancer cell lines. Rational medicinal modifications on gambogic acid will improve its physicochemical properties and drug-like characters. To investigate the structure-activity relationship of gambogic acid and also to find rational modification position on its chemical skeleton, we designed, synthesized, and characterized 16 derivatives of gambogic acid that were modified at C(39). The structure-activity relationships (SARs) were discussed. The anti-proliferation data were accquired through MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays of A549, BGC823, U251, HepG2, and MDA-MB-231 cancer cell lines. Most of the synthesized compounds showed strong inhibitory effects. The SAR study revealed that derivatives with aliphatic amino moieties at C(39) were more potent than those with other substituents. The C(39) position can undergo different kinds of chemical modifications without leading to loss of activity. Compounds 4 and 6 can serve as potential lead compounds for further development of new anticancer drugs.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Garcinia; Humans; Neoplasms; Structure-Activity Relationship; Xanthones

As an oncoprotein, mutant p53 is a potential tumor-specific target for cancer therapy. Most mutated forms of the protein are largely accumulated in cancer cells due to their increased stability. In the present study, we demonstrate that mutant p53 protein stability is regulated by gambogic acid (GA). Following GA exposure, protein levels of mutant p53 decreased while the mRNA levels were not affected in MDA-MB-435 cells, which indicate that GA down-regulates mutant p53 at post-transcription level. Co-treatment with GA and cycloheximide, a protein synthesis inhibitor, induced a decrease of half-life of mutant p53 protein. These findings indicated that the reduction of mutant p53 by GA was due to the destabilization and degradation of the protein. Furthermore, inhibition of proteasome activity by MG132 blocked GA-induced down-regulation of mutant p53, causing mutant p53 accumulation in detergent-insoluble cellular fractions. Further studies revealed that mutant p53 was ubiquitinated and it was chaperones related ubiquitin ligase carboxy terminus of Hsp70-interacting protein (CHIP) rather than MDM2 involved in the degradation of mutant p53. In addition, GA prevented Hsp90/mutant p53 complex formation and enhanced interaction of mutant p53 with Hsp70. Depletion of CHIP stabilized mutant p53 in GA treated cells. In conclusion, mutant p53 may be down-regulated by GA through chaperones-assisted ubiquitin/proteasome degradation pathway in cancer cells.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Survival; Cycloheximide; Humans; Immunohistochemistry; Immunoprecipitation; Mice; Mice, Nude; Neoplasms; Proteasome Endopeptidase Complex; Protein Binding; Protein Synthesis Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases; Xanthones; Xenograft Model Antitumor Assays

Multiple lines of evidence have demonstrated that gambogic acid (GA) is an efficient apoptosis inducing agent. However, the mechanisms of GA induced apoptosis have been controversial, despite the tremendous effort made during recent years. Here we report a novel mechanism through which GA induces cell apoptosis. Instead of dealing with tumor cells directly, GA first activates inactive T lymphocytes, which in turn triggers cancer cell apoptosis. This is supported by the observation that GA inhibited tumor growth and extended the survival time of mice bearing H22 tumor. cDNA microarray analysis indicated that 22.92% of the 48 genes that were affected with GA treatment were immune related genes. RT-PCR assay revealed that GA up-regulated MHC-II and TCR transcriptions, implicating that GA activates T lymphocytes to induce tumor cell apoptosis in vivo. HE staining showed that T lymphocytes penetrated into tumor tissues after GA administration. Western blotting revealed that GA enhanced CD4+ and CD8+ expressions. Annexin-V/PI double-staining and DNA ladder assays confirmed that GA induced tumor cell apoptosis. In summary, this report demonstrated, for the first time, that GA mainly activates T lymphocytes to induce cancer cell apoptosis in H22 transplanted mice.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Gene Expression; Interleukin-2; Lymphocyte Activation; Male; Mice; Neoplasms; Oligonucleotide Array Sequence Analysis; T-Lymphocytes; Xanthones

Gambogic acid (GA) is a natural product with potent apoptotic activity. Here, we showed that GA broadly inhibited the growth of cancer cells that expressed wild-type p53 as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol-iumbromide assay, (3)H-thymidine incorporation analysis, and an in vivo mouse xenograft model. GA induced massive cell apoptosis as judged by Annexin V and propidium iodide dual-staining experiments. Furthermore, we found that GA partially induced cancer cell growth inhibition in a p53-dependent manner because cell survival could be restored after endogenous p53 was attenuated by p53 transcriptional repressor pifithrin-alpha or p53 small interfering RNA. Interestingly, GA had no influence on p53 mRNA synthesis but dramatically enhanced its protein expression. This unique observation could be accounted for by the down-regulation of mdm2 at both mRNA and protein levels. It is concluded that GA enhances p53 protein level through inhibition of mdm2 expression and thereby hampers p53 harboring tumor growth.

Topics: Animals; Annexin A5; Antineoplastic Agents; Apoptosis; Cell Proliferation; Down-Regulation; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasms; Propidium; Proto-Oncogene Proteins c-mdm2; Transcription, Genetic; Tumor Suppressor Protein p53; Up-Regulation; Xanthones; Xenograft Model Antitumor Assays

This study is intended to characterize the cellular target of gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hurburyi tree, which possesses potent in vitro and in vivo antitumor activities. The antiproliferative activity of GA was further confirmed here in a panel of human tumor cells and multidrug-resistant cells. We found that GA significantly inhibited the catalytic activity of topoisomerase (Topo) II and, to a comparatively less extent, of Topo I, without trapping and stabilizing covalent topoisomerase-DNA cleavage complexes. Down-regulation of Topo IIalpha but not Topo I and Topo IIbeta, reduced GA-induced apoptosis and the phosphorylation of c-Jun, and restored cell proliferation upon GA treatment. Moreover, GA antagonized etoposide-induced DNA damage and abrogated the antiproliferative activity of etoposide, whereas it did not affect camptothecin-induced DNA damage. By dissecting the actions of GA on the individual steps of Topo IIalpha catalytic cycle, we found that GA inhibited DNA cleavage and ATP hydrolysis. Moreover, GA directly bound to the ATPase domain of Topo IIalpha, and may share common binding sites with ATP. The results reported here show that GA exerts its antiproliferative effect by inhibiting the catalytic activity Topo IIalpha. They also indicate that GA inhibits Topo IIalpha-mediated DNA cleavage and modulate the activity of Topo II poisons, which provide rationale for further clinical evaluation of GA.

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Antigens, Neoplasm; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Proliferation; DNA Damage; DNA Topoisomerases, Type II; DNA-Binding Proteins; Drug Resistance, Neoplasm; Etoposide; Flow Cytometry; Genes, MDR; HeLa Cells; Humans; Hydrolysis; JNK Mitogen-Activated Protein Kinases; Neoplasms; Phosphorylation; RNA Interference; Surface Plasmon Resonance; Topoisomerase II Inhibitors; Tumor Stem Cell Assay; Xanthones

Transferrin receptor (TfR) has been shown to be significantly overexpressed in different types of cancers. We discovered TfR as a target for gambogic acid (GA), used in traditional Chinese medicine and a previously undiscovered link between TfR and the rapid activation of apoptosis. The binding site of GA on TfR is independent of the transferrin binding site, and it appears that GA potentially inhibits TfR internalization. Down-regulation of TfR by RNA interference decreases sensitivity to GA-induced apoptosis, further supporting TfR as the primary GA receptor. In summary, GA binding to TfR induces a unique signal leading to rapid apoptosis of tumor cells. These results suggest that GA may provide an additional approach for targeting the TfR and its use in cancer therapy.

Topics: Apoptosis; Binding Sites; Cell Line, Tumor; DNA Primers; Drugs, Chinese Herbal; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Microscopy, Electron; Neoplasms; Receptors, Transferrin; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Xanthones