ChemInform Abstract: Design and Synthesis of Gambogic Acid Analogues as Potent Cytotoxic and Antiinflammatory Agents.
Chiao‐Ting YenKyoko Nakagawa‐GotoTsong‐Long HwangSusan L. Morris‐NatschkeKenneth F. BastowYang‐Chang WuKuo‐Hsiung Lee
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Abstract Prenyl‐ and pyrano‐xanthones derived from xanthenone (III), a basic backbone of gambogic acid, are synthesized and screened for in vitro cytotoxic effects against four human cancer cell lines and anti‐inflammatory activity.Keywords:
Gambogic acid
Gambogic acid
Natural product
Lead compound
Structure–activity relationship
Chemical structure
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Gambogic acid,the natural compound extract from gamboges,might be a kind of highly effective anticancer drug candidate with low toxicity to normal tissue.In this review,we conclude that gambogic acid mainly can cause cell cycle arrest,induce cancer cell apoptosis,repress telomerase and Topo Ⅱalpha,possess the high antiangiogenic activities and antiinvasion properties,and reverse multidrug resistance.
Gambogic acid
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HER2 positive breast cancer is one of the biggest health problems in the world, causing millions of deaths every year. Drug combination modeling studies are extensively evaluated in treating many diseases. Pharmacological studies over the last half-century have shown that gambogic acid has potent anti-tumor activity against many types of cancer, including breast cancer. In this study, we examined the synergistic anticancer effect of gambogic acid and trastuzumab in HER2 positive breast cancer cell line (MDA-MB-453). In-vitro synergistic and antiproliferative effects of trastuzumab plus gambogic acid studies were determined with XTT method and the combination index (CI) values of the trastuzumab and gambogic acid combination were calculated by CompuSyn software. To determine molecular mechanisms of the trastuzumab and gambogic acid combination, we analyzed HER2, caspase-9 and Bax gene and protein expression levels quantitative reverse transcription-PCR (qRT-PCR) and ELISA techniques. The combination of 50 µg/ml trastuzumab and 5 µM gambogic acid showed the best synergistic effect at 24 h incubation in MDA-MB-453 cells according to the in-vitro cell proliferation, RT-qPCR and ELISA test. Gambogic acid effects on HER2 positive breast cancer cell line shows its potential as natural compound to inhibit breast cancer cell proliferation in combination with trastuzumab.
Gambogic acid
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The isolation of gambogic acid is described. Reactions of gambogic acid are discussed and it is shown that some reactions involve isomeric change in the molecule. The possible relationship of gambogic acid to morellin is considered, the substitution pattern being examined in detail, and a structure is assigned which is consistent with much of the known chemistry of gambogic acid.
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Objective To study the inducing differentiation effect of gambogic acid.Methods Inducing differentiation effect of gambogic acid were evaluated by proliferation,morphology and function of tumor cells.Results Hb content of K562 cell was increased,melanin content of B16 cell was decreased and proliferation of Bel 7402 cell was inhibited by gambogic acid.And Bel 7402 cell showed induce differentiation in morphology.Conclusion Gambogic acid has inducing differentiation effect on tumor cells.
Gambogic acid
K562 cells
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Experimental study on gambogic acid-induced gastric cancer cell apoptosis and anti-tumor metastasis.
Objective To investigate the inhibition of gambogic acid on proliferation and metastasis ability of BGC-803 cells and to study their preliminary mechanism further.Methods Methyl thiazolyl tetrazolium(MTT) and Hoechst staining were used to study the effects of gambogic acid-induced apoptosis in gastric cancer cell line BGC-803;Invasive methods were used to study the effects of invasion,adhesion,migration by gambogic acid;The influence of gambogic acid on the expression of bcl-2,bax,and ICAM-1 gene in gastric cancer cells was evaluated by RT-PCR and Western-blotting.Results Gambogic acid was found not only to inhibit the growth of BGC-803 cells but also to induce the cell apoptosis in a dose-and time-dependent manner.The ability of adhesion,migration,and invasiveness was clearly inhibited by gambogic acid.With the increase of gambogic acid concentration,the expression of bcl-2,ICAM-1 gene,and protein were down-regulated and the expression of bax gene and protein were up-regulated.ConclusionGambogic acid could inhibit the growth of gastric cancer cells BGC-803 significantly,have a significant role in promoting tumor cell apoptosis,and inhibit tumor cell metastasis-associated properties.The mechanism may be related to decrease of bcl-2,ICAM-1 expression and increase bax expression.
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Objective:To assess the natural interaction between gambogic acid and oxaliplatin widely used in gastrointestinal cancer treatment,and to investigate the influence of gambogic acid on cell apoptosis and drug-associated gene expression. Methods:Synergistic interaction on human gastric cancer cell lines BGC-823 and MKN-28 was evaluated using the combination index (CI) method. The double staining with both Annexin-Ⅴ-FITC and PI was employed to distinguish the apoptotic cells from others. Expression of drug- associated genes,i.e.,excision repair cross-complementing(ERCC1),breast cancer susceptibility gene 1(BRCA1) of BGC-823 with or without gambogic acid treatment were measured by real-time quantitative RT-PCR. Results:Gambogic acid had a synergistic effect on the cytotoxicity of oxaliplatin in BGC-823 cells. The combination of gambogic acid and oxaliplatin could also induce apoptosis in a synergistic manner. Most prominently,ERCC1,BRCA1 mRNA levels of BGC-823 were markedly suppressed at 0.070-,and 0.140-fold respectively by the presentation of gambogic acid. Conclusion:Gambogic acid appears a promising candidate for combining with oxaliplatin in cancer chemotherapy treatment. The possible synergistic mechanisms maybe the synergistic apoptotic effect and the downregulation of drug-associated genes.
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Gambogic acid
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Aim To detect the stability of solid lipid nanoparticle in rat plasma.Methods Through detecting and contrasting the leakage rate of neo-gambogic acid reference solution and neo-gambogic acid SLN by HPLC,the stability of neo-gambogic acid SLN in rat plasma was examined.Results The leakage rate of neo-gambogic acid reference solution was 71.2%,and the neo-gambogic acid SLN was 38.5%.Conclusion Neo-gambogic acid SLN has higher stability than neo-gambogic reference solution.
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This study was aimed to investigate the effects of gambogic acid on the cells of high-risk patients with myelodysplastic syndrome (MDS) in vitro and its mechanism. The inhibition effect of gambogic acid on growth of MUTZ-1 cell line of MDS-RAEB was detected by MTT method. Apoptosis and cell cycle were detected by morphological observation and flow cytometry respectively. The expressions of bax/bcl-2 gene at mRNA level were detected by RT-PCR. The results indicated that the Gambogic acid inhibited the growth of MUTZ-1 cells, the inhibitory rate of gambogic acid with the range of 0.2 - 0.8 microg/ml was enhanced along with increasing of drug concentration. Flow cytometric assay showed that the apoptotic rate of MUTZ-1 cells treated by gambogic acid also was enhanced along with increasing of drug concentration, the apoptotic rates resulting from gambogic acid (0, 0.4, 0.6, 0.8 microg/ml) were (5 +/- 0.5)%, (13 +/- 0.5)%, (37 +/- 0.7)% and (56 +/- 0.6)% respectively. The characteristic changes of apoptosis emerged in MUTZ-1 cells after being exposed to gambogic acid. Gambogic acid could significantly down-regulate the expressions of bcl-2 gene in a dose dependent manner, however, it had no effects on bax gene. It is concluded that within the range of concentration from 0.4 to 0. 8 microg/ml, gambogic acid can inhibit the growth of MUTZ-1 cells by inducing their apoptosis and down-regulating the expression of bcl-2 gene, which may be one of the main mechanisms underlying its antitumor effects.
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