GA3, a new gambogic acid derivative, exhibits potent antitumor activities in vitro via apoptosis-involved mechanisms  

作　　者：Hua XIE Yu-xin QIN Yun-long ZHOU Lin-jiang TONG Li-ping LIN Mei-yu GENG Wen-hu DUAN Jian DING 

机构地区：[1]Division of Antitumor Pharmacology ,State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]Department of MedicinaI Chemistry State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

出　　处：《Acta Pharmacologica Sinica》2009年第3期346-354,共9页中国药理学报（英文版）

基　　金：Acknowledgement This work was financially supported by the National Natural Science Foundation of China （No 30721005）. Hua XIE especially appreciated the support from a Shanghai Postdoctoral Grant （No 05R214157）.

摘　　要：Aim： Gambogic acid （GA） is the major active ingredient of gamboge, which is secreted from a Chinese traditional medicine, Garcinia hanburyi, which possesses potent antitumor activity. GA3, a new GA derivative, has been shown to possess better water solubility than GA. The aim of the present study was to examine the antitumor activity of GA3 and the mechanism underlying it. Methods： The growth inhibition of cancer cell lines induced by GA3 was assessed using the SRB assay. DAPI staining, flow cytometry, a DNA fragment assay, and Western blot analysis were used to study the apoptotic mechanisms of GA3. Results： GA3 displayed wide cytotoxicity in diversified human cancer cell lines with a mean ICs0 value of 2.15 μmol/L. GA3 was also effective against multidrug resistant cells, with an average resistance factor （RF） that was much lower than that of the reference drug, doxorubicin. Mechanistic studies revealed that GA3-induced apoptosis in HL-60 cells proceeded via both extrinsic and intrinsic pathways, with caspase-8 functioning upstream of caspase-9. In addition, GA3-driven apoptotic events were associated with up-regulation of Bax, down-regulation of Bcl-2 and cleavage of Bid. Moreover, GA3 triggered cytochrome c release from the mitochondria, in particular bypassing the involvement of the mitochondrial membrane potential. Conclusion： Better solubility and a potential anti-MDR activity, combined with a comparable antitumor efficacy, make GA3 a potential drug candidate in cancer therapy that deserves further investigation.Aim： Gambogic acid （GA） is the major active ingredient of gamboge, which is secreted from a Chinese traditional medicine, Garcinia hanburyi, which possesses potent antitumor activity. GA3, a new GA derivative, has been shown to possess better water solubility than GA. The aim of the present study was to examine the antitumor activity of GA3 and the mechanism underlying it. Methods： The growth inhibition of cancer cell lines induced by GA3 was assessed using the SRB assay. DAPI staining, flow cytometry, a DNA fragment assay, and Western blot analysis were used to study the apoptotic mechanisms of GA3. Results： GA3 displayed wide cytotoxicity in diversified human cancer cell lines with a mean ICs0 value of 2.15 μmol/L. GA3 was also effective against multidrug resistant cells, with an average resistance factor （RF） that was much lower than that of the reference drug, doxorubicin. Mechanistic studies revealed that GA3-induced apoptosis in HL-60 cells proceeded via both extrinsic and intrinsic pathways, with caspase-8 functioning upstream of caspase-9. In addition, GA3-driven apoptotic events were associated with up-regulation of Bax, down-regulation of Bcl-2 and cleavage of Bid. Moreover, GA3 triggered cytochrome c release from the mitochondria, in particular bypassing the involvement of the mitochondrial membrane potential. Conclusion： Better solubility and a potential anti-MDR activity, combined with a comparable antitumor efficacy, make GA3 a potential drug candidate in cancer therapy that deserves further investigation.

关 键 词：gambogic acid GA3 ANTITUMOR APOPTOSIS CASPASE Bcl-2 cytochrome c 

分 类 号：R378.25[医药卫生—病原生物学] R979.1[医药卫生—基础医学]