Potentiation of arsenic trioxide-induced apoptosis by 8-bromo-7-methoxychrysin in human leukemia cells involves depletion of intracellular reduced glutathione  

作　　者：Guangfen Xiao Xueyuan Tang Chenjiao Yao Chenghong Wang 

机构地区：[1]Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha 410013, China

出　　处：《Acta Biochimica et Biophysica Sinica》2011年第9期712-721,共10页生物化学与生物物理学报（英文版）

基　　金：This work was supported by grants from the Hunan Provincial Natural Science Foundation of China （2009JJ3067）, the Project of Hunan Provincial Science and Technology Department （2009SK3173）, and the Hunan Provincial Development and Reform Commission of China.

摘　　要：The novel chrysin analog 8-bromo-7-methoxychrysin （BrMC） has been reported to induce apoptosis of various cancer cell lines. Arsenic trioxide （ATO） treatment induces clinical remission in acute promyelocytic leukemia patients. The combination of ATO with other agents has been shown to improve therapeutic effectiveness in vitro and in vivo. In this report, the mechanism of apoptosis induced by treatment with ATO alone or in combination with BrMC was studied in U937, HL-60, and Jurkat ceils. Our results demonstrated that BrMC cooperated with ATO to induce apoptosis in human leukemia cells. This co-treatment caused mitochondrial transmembrane potential dissipation and stimulated the mitochondrial apoptotic pathway, as evidenced by cytochrome c release, down-regulation of X-linked inhibitor of apoptosis （XIAP） and BcI-XL, and up-regulation of Bax. BrMC alone or in combination with ATO, decreased Akt phosphorylation as well as intracellular reduced glutathione （GSH） content. The thiol antioxidant N-acetylcysteine and exogenous GSH restored GSH content and attenuated apoptosis induced by co-treatment with ATO plus BrMC. In contrast, the non-thiol antioxidant butylated hydroxyanisole and mannitol failed to do so. These findings suggest that GSH depletion explains at least in part the potentiation of ATO-induced apoptosis by BrMC.The novel chrysin analog 8-bromo-7-methoxychrysin （BrMC） has been reported to induce apoptosis of various cancer cell lines. Arsenic trioxide （ATO） treatment induces clinical remission in acute promyelocytic leukemia patients. The combination of ATO with other agents has been shown to improve therapeutic effectiveness in vitro and in vivo. In this report, the mechanism of apoptosis induced by treatment with ATO alone or in combination with BrMC was studied in U937, HL-60, and Jurkat ceils. Our results demonstrated that BrMC cooperated with ATO to induce apoptosis in human leukemia cells. This co-treatment caused mitochondrial transmembrane potential dissipation and stimulated the mitochondrial apoptotic pathway, as evidenced by cytochrome c release, down-regulation of X-linked inhibitor of apoptosis （XIAP） and BcI-XL, and up-regulation of Bax. BrMC alone or in combination with ATO, decreased Akt phosphorylation as well as intracellular reduced glutathione （GSH） content. The thiol antioxidant N-acetylcysteine and exogenous GSH restored GSH content and attenuated apoptosis induced by co-treatment with ATO plus BrMC. In contrast, the non-thiol antioxidant butylated hydroxyanisole and mannitol failed to do so. These findings suggest that GSH depletion explains at least in part the potentiation of ATO-induced apoptosis by BrMC.

关 键 词：arsenic trioxide CHRYSIN 8-bromo-7- methoxychrysin apoptosis GSH leukemia cells 

分 类 号：Q26[生物学—细胞生物学] X503.225[环境科学与工程—环境工程]