Gambogic acid

The herbs of Garcinia hanburyi Hook. f.

Gambogic acid (GA) is an inducer of apoptosis with EC50 value of 0.78-1.64 μM for caspases and with IC50 values of 1.47, 1.21, 2.02, 0.66, 1.06 and 0.79 μM for Bcl-XL, Bcl-2, Bcl-W, Bcl-B, Bfl-1 and Mcl-1, respectively [1].

The cytotoxic natural product GA competes for BH3 peptide binding sites on several antiapoptotic members of the Bcl-2 family and neutralizes the ability of these proteins to suppress release of apoptogenic proteins from mitochondria.

In vitro, it was demonstrated that GA inhibited the proliferation of human gastric carcinoma MGC-803 cells in a dose-dependent manner. When the cells were exposed to GA 5 mg/ml for 72 h, the rate of inhibition reached 89.45%. The IC50 value was 0.96 mg/ml at 48 h. In addition, GA can’t induce cell death in normal unimmortalized cells, but it can selectively kill the tumor cells. Treatment with GA at concentrations above 0.4 μM led to a significant dose-dependent inhibition of U266 cell growth under normoxia and hypoxia when U266 cells exposed to GA under normoxia and hypoxia for 8 h [2, 3].

Using a prostate cancer xenograft model, s.c. injection daily for 15 days was reported that GA effectively inhibited tumor angiogenesis and suppressed tumor growth with few side effects. And using a mouse model of glioma, i.v. injection of GA daily for 14 days was reported to significantly reduce tumor volumes with little side effects. The effects of GA on expression of HIF-1a and its downstream target gene vascular endothelial growth factor was investigated in human MM U266 cells. Tumor xenografts transplanted by U266 cells were used to test the antitumor effect of GA in BALB ?c nude mice in vivo. After a treatment of 14-day, the tumors were moved and photographed. The results indicated that GA significantly inhibited tumor growth in a dosage-dependent manner. After exposure of MGC-803 cells to GA (1 μg/ml) for 24, 48, and 72 h, the apoptosis rate was 38.56, 73.70, and 71.77%, respectively. A number of MGC-803 cells turned round in shape and necrosed, while the untreated cells grew well and the skeleton was clear after cultured with GA 1mg/ml for 48 h [1, 3].

References:
[1].  Zhai DY, Jin CF, Shiau CW, et al. Gambogic acid is an antagonist of antiapoptotic Bcl-2 family proteins. Molecular Cancer Therapeutics, 2008, 7(6): 329-340.
[2].  Zhao L, Guo QL, You QD, et al. Gambogic acid induces apoptosis and regulates expressions of Bax and Bcl-2 protein in human gastric carcinoma MGC-803 cells. Biological & Pharmaceutical Bulletin, 2004, 27(7): 998-1003.
[3].  Wang F, Zhang W, Guo LT, et al. Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1/vascular endothelial growth factor expression via inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma cells. Cancer Science, 2014, 105(8): 1063-1070.

Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibition through AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells.[Pubmed:23665322]

Biochem Biophys Res Commun. 2013 Jun 7;435(3):397-402.

Glioblastoma multiforme (GBM) is the most common malignant tumor in adults' central nervous system (CNS). The development of novel anti-cancer agents for GBM is urgent. In the current study, we found that Gambogic acid induced growth inhibition and apoptosis in cultured U87 glioma cells, which was associated with Akt/mTORC1 (mTOR complex 1) signaling in-activation. To restore Akt activation by introducing a constitutively active (CA) Akt attenuated Gambogic acid-induced cytotoxicity against U87 cells. For mechanism study, we found that Gambogic acid induced LRIG1 (leucine-rich repeat and Ig-like domain-containing-1) upregulation, which was responsible for EGFR (epidermal growth factor receptor) degradation and its downstream Akt/mTORC1 inhibition. Further, we provided evidence to support that AMPK (AMP-activated protein kinase) activation mediated Gambogic acid-induced LRIG1 upregulation, U87 cell apoptosis and growth inhibition, while AMPK inhibition by shRNA or compound C reduced Gambogic acid-induced EGFR/Akt inhibition and cytotoxicity in U87 cells. We here proposed novel signaling mechanism mediating Gambogic acid-induced cytotoxic effects in glioma cells.

Gambogic acid sensitizes ovarian cancer cells to doxorubicin through ROS-mediated apoptosis.[Pubmed:23436279]

Cell Biochem Biophys. 2013 Sep;67(1):199-206.

Ovarian cancer is one human malignancy which has response portly to doxorubicin. The anti-cancer activity of Gambogic acid has been tested in in vitro and in vivo studies. In this study, we showed that Gambogic acid, a natural compound, could potentiate the anticancer activity of doxorubicin in ovarian cancer through ROS-mediated apoptosis. Platinum-resistant human ovarian cancer cell line (SKOV-3) was treated with Gambogic acid, doxorubicin, or the combination of both to investigate cell proliferation and apoptosis. We found that the combination of Gambogic acid and doxorubicin causes synergistic loss of cell viability in SKOV-3 cells and this synergistic effect correlated with increased cellular ROS accumulation. Moreover, in vivo results showed that Gambogic acid and doxorubicin combination resulted in a synergistic suppressing effect on tumor growth in ovarian cancer mice model. Taken together, the results suggested that doxorubicin in combination with Gambogic acid might provide a promising therapeutic strategy to enhance chemosensitivity of ovarian cancer to doxorubicin.

Gambogic acid is a tissue-specific proteasome inhibitor in vitro and in vivo.[Pubmed:23260670]

Cell Rep. 2013 Jan 31;3(1):211-22.

Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment.

Potent anti-inflammatory and antiproliferative effects of gambogic acid in a rat model of antigen-induced arthritis.[Pubmed:24623960]

Mediators Inflamm. 2014;2014:195327.

BACKGROUND: We have previously reported a continuous activation of caspase-1 and increased interleukin (IL)-1beta levels in early rheumatoid arthritis (RA). These observations raised the hypothesis that drugs targeting the IL-1beta pathway, in addition to tumour necrosis factor (TNF), may be particularly effective for early RA treatment. We have recently identified Gambogic acid as a promising therapeutic candidate to simultaneously block IL-1beta and TNF secretion. Our main goal here was to investigate whether Gambogic acid administration was able to attenuate inflammation in antigen-induced arthritis (AIA) rats. METHODS: Gambogic acid was administered to AIA rats in the early and late phases of arthritis. The inflammatory score, ankle perimeter, and body weight were evaluated during the period of treatment. Rats were sacrificed after 19 days of disease progression and paw samples were collected for histological and immunohistochemical evaluation. RESULTS: We found that inflammation in joints was significantly suppressed following Gambogic acid administration. Histological and immunohistochemical evaluation of treated rats revealed normal joint structures with complete abrogation of the inflammatory infiltrate and cellular proliferation. CONCLUSIONS: Our results suggest that Gambogic acid has significant anti-inflammatory properties and can possibly constitute a prototype anti-inflammatory drug with therapeutic efficacy in the treatment of inflammatory diseases such as RA.

Gambogic acid induced oxidative stress dependent caspase activation regulates both apoptosis and autophagy by targeting various key molecules (NF-kappaB, Beclin-1, p62 and NBR1) in human bladder cancer cells.[Pubmed:25218692]

Biochim Biophys Acta. 2014 Dec;1840(12):3374-84.

BACKGROUND: Gambogic acid is a potent anticancer agent and has been found effective against various types of cancer cells. The present study was addressed to explore the cytotoxic potential of Gambogic acid and the modulation of autophagy and apoptosis in bladder cancer cells T24 and UMUC3. METHODS: Bladder cancer cell lines T24 and UMUC3 were treated with Gambogic acid, apoptosis was checked by flow-cytometry and expression of various autophagy and apoptosis related proteins was monitored by Western blotting. Confocal microscope was used for colocalization of p62 and Beclin-1. RESULTS: Gambogic acid induces reactive oxygen species, and elicits a strong autophagic response by activating JNK at earlier time points, which is inhibited at later time points with the activation of caspases. Reactive oxygen species mediated caspase activation causes degradation of autophagic proteins, cleavage of molecular chaperones (Hsp90 and GRP-78) and adaptor proteins (p62 and NBR1). Gambogic acid treatment results in mitochondrial hyperpolarization and cytochrome c release and activates caspases involved in both extrinsic and intrinsic apoptotic pathways. Gambogic acid abrogates NF-kappaB activation by ROS mediated inhibition of IkappaB-alpha phosphorylation. Functionally Gambogic acid induced autophagy acts as a strong cell survival response and delays caspase activation. CONCLUSION: Our study provides the new insights about the mechanism of Gambogic acid induced modulation of autophagy and apoptosis in bladder cancer cells. All the molecular events responsible for Gambogic acid induced autophagy and apoptosis are mediated by reactive oxygen species. GENERAL SIGNIFICANCE: Since Gambogic acid targets various cell survival molecules therefore, it may be considered as a potential anticancer agent against bladder cancer.

Gambogic acid inhibits angiogenesis and prostate tumor growth by suppressing vascular endothelial growth factor receptor 2 signaling.[Pubmed:18339865]

Cancer Res. 2008 Mar 15;68(6):1843-50.

Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been previously reported to activate apoptosis in many types of cancer cell lines by targeting transferrin receptor and modulating nuclear factor-kappaB signaling pathway. Whether GA inhibits angiogenesis, which is crucial for cancer and other human diseases, remains unknown. Here, we found that GA significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, invasion, tube formation, and microvessel growth at nanomolar concentration. In a xenograft prostate tumor model, we found that GA effectively inhibited tumor angiogenesis and suppressed tumor growth with low side effects using metronomic chemotherapy with GA. GA was more effective in activating apoptosis and inhibiting proliferation and migration in HUVECs than in human prostate cancer cells (PC3), suggesting GA might be a potential drug candidate in cancer therapy through angioprevention with low chemotoxicity. Furthermore, we showed that GA inhibited the activations of vascular endothelial growth factor receptor 2 and its downstream protein kinases, such as c-Src, focal adhesion kinase, and AKT. Together, these data suggest that GA inhibits angiogenesis and may be a viable drug candidate in antiangiogenesis and anticancer therapies.

Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent Bcr-Abl downregulation.[Pubmed:24334603]

Clin Cancer Res. 2014 Jan 1;20(1):151-63.

PURPOSE: Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl-T315I is the predominant mutation that causes resistance to imatinib, cytotoxic drugs, and the second-generation tyrosine kinase inhibitors. The emergence of imatinib resistance in patients with CML leads to searching for novel approaches to the treatment of CML. Gambogic acid, a small molecule derived from Chinese herb gamboges, has been approved for phase II clinical trial for cancer therapy by the Chinese Food and Drug Administration (FDA). In this study, we investigated the effect of Gambogic acid on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. EXPERIMENTAL DESIGN: CML cell lines (KBM5, KBM5-T315I, and K562), primary cells from patients with CML with clinical resistance to imatinib, and normal monocytes from healthy volunteers were treated with Gambogic acid, imatinib, or their combination, followed by measuring the effects on cell growth, apoptosis, and signal pathways. The in vivo antitumor activity of Gambogic acid and its combination with imatinib was also assessed with nude xenografts. RESULTS: Gambogic acid induced apoptosis and cell proliferation inhibition in CML cells and inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Our data suggest that GA-induced proteasome inhibition is required for caspase activation in both imatinib-resistant and -sensitive CML cells, and caspase activation is required for Gambogic acid-induced Bcr-Abl downregulation and apoptotic cell death. CONCLUSIONS: These findings suggest an alternative strategy to overcome imatinib resistance by enhancing Bcr-Abl downregulation with the medicinal compound Gambogic acid, which may have great clinical significance in imatinib-resistant cancer therapy.

Combined therapy with EGFR TKI and gambogic acid for overcoming resistance in EGFR-T790M mutant lung cancer.[Pubmed:26622796]

Oncol Lett. 2015 Oct;10(4):2063-2066.

Although patients with non-small cell lung cancer (NSCLC) experience an initial response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, those individuals with activating mutations in EGFR develop resistance. Gambogic acid (GA), a polyprenylated xanthone, has strong antitumor activities. In the present study, the therapeutic efficacy of gefitinib with GA was evaluated in a gefitinib-resistant NSCLC model. The NCI-H1975 cell line with EGFR-T790M mutation was subcutaneously injected into immunocompromised mice. The mice were randomly assigned to receive treatment with gefitinib, GA, gefitinib plus GA, or vehicle for 4 weeks, then all mice were sacrificed and their tumor tissues were subjected to caspase activity detection and western blot analysis. Gefitinib and GA alone slightly inhibited the tumor growth of NCI-H1975. However, the combined treatment significantly enhanced their antitumor effects, without any marked adverse events. In addition, gefitinib plus GA enhanced the level of apoptosis in the tumor tissues. Western blot analysis also revealed that the combination treatment reduced the phosphorylation level of AKT, MEK1/2 and ERK1/2, while an increased expression ratio of Bax/Bcl-2 was observed. In the current study, gefitinib in combination with GA resulted in antitumor growth in the EGFR-T790M secondary mutation NCI-H1975 tumor model due to an enhanced apoptotic effect. This novel therapeutic strategy may be a practical approach for the treatment of patients who show gefitinib resistance.

Specific and slow inhibition of the kir2.1 K+ channel by gambogic acid.[Pubmed:19366693]

J Biol Chem. 2009 Jun 5;284(23):15432-8.

Although Kir2.1 channels are important in the heart and other excitable cells, there are virtually no specific drugs for this K+ channel. In search of Kir2.1 modulators, we screened a library of 720 naturally occurring compounds using a yeast strain in which mammalian Kir2.1 enables growth at low [K+]. One of the identified compounds, Gambogic acid (GA), potently (EC(50) < or = 100 nm) inhibited Kir2.1 channels in mammalian cells when applied chronically for 3 h. This potent and slow inhibition was not seen with Kv2.1, HERG or Kir1.1 channels. However, acutely applied GA acted as a weak (EC(50) = approximately 10 mum) non-selective K+ channel blocker. Intracellular delivery of GA via a patch pipette did not potentiate the acute effect of GA on Kir2.1, showing that slow uptake is not responsible for the delayed, potent effect. Immunoblots showed that total Kir2.1 protein expression was not altered by GA. Similarly, immunostaining of intact cells expressing Kir2.1 with an extracellular epitope tag demonstrated that GA does not affect Kir2.1 surface expression. However, the 3-h treatment with GA caused redistribution of Kir2.1 and Kv2.1 from the Triton X-100-insoluble to the Triton X-100-soluble membrane fraction. Thus, GA changes the K+ channel membrane microenvironment resulting in potent, specific, and slow acting inhibition of Kir2.1 channels.

Anti-invasive effect of gambogic acid in MDA-MB-231 human breast carcinoma cells.[Pubmed:18923540]

Biochem Cell Biol. 2008 Oct;86(5):386-95.

Gambogic acid (GA) has been known to have antitumor activity in vitro and in vivo. In the present study, we investigated the anti-invasive effects of GA in MDA-MB-231 human breast carcinoma cells. The results indicated that GA significantly inhibited the adhesion, migration, and invasion of the cells in vitro tested by the heterotypic adhesion assay, wound migration assay, and chamber invasion assay. Results of Western blotting and immunocytochemistry analysis showed that GA could suppress the expressions of matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9) in MDA-MB-231 cells. Furthermore, gelatin zymography revealed that GA decreased the activities of MMP-2 and MMP-9. Additionally, GA exerted an inhibitory effect on the phosphorylation of ERK1/2 and JNK, while it had no effect on p38. Taken together, our results demonstrated the anti-invasive property of GA for the first time and indicated it could serve as a promising drug for the treatment of cancer metastasis.

Gambogic acid is an antagonist of antiapoptotic Bcl-2 family proteins.[Pubmed:18566235]

Mol Cancer Ther. 2008 Jun;7(6):1639-46.

The natural product Gambogic acid (GA) has been reported to have cytotoxic activity against tumor cells in culture and was identified as an active compound in a cell-based high-throughput screening assay for activators of caspases, proteases involved in apoptosis. Using the antiapoptotic Bcl-2 family protein, Bfl-1, as a target for screening of a library of natural products, we identified GA as a competitive inhibitor that displaced BH3 peptides from Bfl-1 in a fluorescence polarization assay. Analysis of competition for BH3 peptide binding revealed that GA inhibits all six human Bcl-2 family proteins to various extents, with Mcl-1 and Bcl-B the most potently inhibited [concentrations required for 50% inhibition (IC(50)), < 1 micromol/L]. Competition for BH3 peptide binding was also confirmed using a time-resolved fluorescence resonance energy transfer assay. GA functionally inhibited the antiapoptotic Bcl-2 family proteins as shown by experiments using isolated mitochondria in which recombinant purified Bcl-2 family proteins suppress SMAC release in vitro, showing that GA neutralizes their suppressive effects on mitochondria in a concentration-dependent manner. GA killed tumor cell lines via an apoptotic mechanism, whereas analogues of GA with greatly reduced potency at BH3 peptide displacement showed little or no cytotoxic activity. However, GA retained cytotoxic activity against bax-/-bak-/- cells in which antiapoptotic Bcl-2 family proteins lack a cytoprotective phenotype, implying that GA also has additional targets that contribute to its cytotoxic mechanism. Altogether, the findings suggest that suppression of antiapoptotic Bcl-2 family proteins may be among the cytotoxic mechanisms by which GA kills tumor cells.

Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay.[Pubmed:14723951]

Bioorg Med Chem. 2004 Jan 15;12(2):309-17.

Gambogic acid (2), a natural product isolated from the resin of Garcinia hurburyi tree, was discovered to be a potent apoptosis inducer using our cell- and caspase-based high-throughput screening assays. Gambogic acid was found to have an EC(50) of 0.78 microM in the caspase activation assay in T47D breast cancer cells. The apoptosis-inducing activity of Gambogic acid was further characterized by a nuclear fragmentation assay and flow cytometry analysis in human breast tumor cells T47D. Gambogic acid was found to induce apoptosis independent of cell cycle, which is different from paclitaxel that arrests cells in the G2/M phase. To understand the structure-activity relationship (SAR) of Gambogic acid, derivatives of 2 with modifications to different function groups were prepared. SAR studies of Gambogic acid, as measured by the caspase activation assay, showed that the 9,10 carbon-carbon double bond of the alpha,beta-unsaturated ketone is important for biological activity, while the 6-hydroxy and 30-carboxy group can tolerate a variety of modifications. The importance of the 9,10 carbon-carbon double bond was confirmed by the traditional growth inhibition assay. The high potency of 2 as an inducer of apoptosis, its novel mechanism of action, easy isolation and abundant supply, as well as the fact that it is amenable to chemical modification, makes Gambogic acid an attractive molecule for the development of anticancer agents.

Gambogic Acid (Beta-Guttiferrin) is derived from the gamboges resin of the tree Garcinia hanburyi. Gambogic Acid (Beta-Guttiferrin) inhibits Bcl-XL, Bcl-2, Bcl-W, Bcl-B, Bfl-1 and Mcl-1 with IC50s of 1.47 μM, 1.21 μM, 2.02 μM, 0.66 μM, 1.06 μM and 0.79 μM.

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