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力达霉素经线粒体依赖通路介导细胞凋亡 被引量:16

Effect of lidamycin on mitochondria initiated apoptotic pathway in human cancer cells
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摘要 力达霉素(lidamycin,LDM)是具有我国自主知识产权的烯二炔类抗生素,具有较强的抗肿瘤活性,其抗肿瘤机制有待深入阐明。本研究主要利用人肝癌BEL-7402和乳腺癌MCF-7细胞研究了力达霉素对线粒体凋亡通路相关因子的影响。通过MTT法检测不同剂量力达霉素对肿瘤细胞增殖毒性;蛋白印迹技术检测线粒体和细胞质细胞色素c、总Bax,Bcl-2及p53表达;RT-PCR检测p53和baxmRNA表达等。结果发现,LDM能迅速激活肿瘤细胞线粒体凋亡通路,在2h内就引起线粒体中细胞色素c释放至细胞质中。同时Bcl-2家族成员中促凋亡成员Bax持续增加,而抗凋亡成员Bcl-2先增加后减少。p53蛋白在6h显著增加。Bax蛋白表达升高与其mRNA转录水平升高有关,p53蛋白表达升高与转录后水平有关。Caspase抑制剂可以部分抑制LDM的增殖毒性。因此LDM可以通过激活细胞色素c启动的线粒体凋亡通路发挥抗肿瘤作用。 Although enediyne antibiotic lidamycin (LDM) is a potent inducer of apoptosis, the underlying mechanisms of its apoptotic functions remain to be explored. Here, we aim to elucidate its possible mechanisms in mitochondria initiated apoptotic pathway involved in human BEL-7402 and MCF-7 cells. Cytochrome c released from mitchondria to cytosol fraction was detected by Western blotting, p53 and Bax, Bcl-2 expressions were detected by Western blotting and RT-PCR. MTT assay was used to detect cytotoxicity of LDM with or without caspase inhibitor z-VAD-fmk. After the BEL-7402 cells were exposed to 0. 1μmol·L^-1 LDM within 6 h, the increase of cytochrome c in the cytosol and decrease in the mitochondria were observed when compared with untreated cells. The expression of Bax, an important proapoptotic member of the Bcl-2 family, increased gradually in the BEL-7402 cells after exposure to LDM of 0. 1 μmol·L^-1 for 2, 6, and 9 h, separately, while Bcl-2 increased at 2 and 6 h, and decreased at 9 h after LDM treatment. Enhanced protein expressions were parallel with respective increased mRNA level for Bax only, but not p53. Caspase inhibitor may inhibit partially the killing effects induced by LDM. Therefore we conclude that the rapid activation of mitochondrial pathway induced by LDM in tumor cells might contribute to its highly potent cytotoxicities.
出处 《药学学报》 CAS CSCD 北大核心 2007年第2期132-138,共7页 Acta Pharmaceutica Sinica
基金 国家自然科学基金资助项目(30300424 30572204 30472042).
关键词 力达霉素 线粒体 肿瘤 细胞凋亡 lidamycin mitochondria tumor apoptosis
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参考文献19

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