Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma
Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma
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DOI：
10.4161/cbt.6.2.3626
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发表时间：
2007-02-01
影响因子：
3.6
通讯作者：
Smythe, W. Roy
中科院分区：
文献类型：
--
作者：
Cao, Xiaobo;Rodarte, Charles;Smythe, W. Roy
间皮瘤是一种胸膜肿瘤，目前无法治愈的传统疗法。先前，我们证明间皮瘤过表达BCL - 2家族的抗凋亡成员BCL-X-L。此外，我们已经表明，使用BCL-X-L反义寡核苷酸下调BCL-X-L在体外和体内引起间皮瘤凋亡细胞死亡。本研究的目的是评价bcl 2/bcl-x（L）抑制剂2 -甲氧基抗霉素A3在体内外诱导细胞凋亡和增加化疗敏感性的作用。将几种bcl-x（L）高表达肿瘤细胞系和一种正常人细胞系暴露于2 -甲氧基抗霉素A3。2 -甲氧基抗霉素A3仅在这些肿瘤细胞系中表现出显著的生长抑制作用，对正常人细胞几乎没有影响。单独用2 -甲氧基抗霉素A3处理导致癌细胞中凋亡诱导的显著增加。细胞凋亡通过降低线粒体膜电位和半胱天冬酶激活而发生。值得注意的是，用2 -甲氧基抗霉素A3治疗不改变BCL - 2家族蛋白表达。在体外和体内实验中观察到顺铂和2 -甲氧基抗霉素A3的联合给药对肿瘤生长的协同抑制作用。总之，这些发现表明，将癌细胞暴露于小分子Bcl-2/x（L）抑制剂如2 -甲氧基抗霉素A3单独或与其他化疗剂组合，可能代表治疗癌症，特别是间皮瘤的新治疗策略。
Meosthelioma is a neoplasm of the pleura that is currently incurable by conventional therapies. Previously, we demonstrated that mesothelioma overexpresses BCL-X-L, an anti - apoptotic member of the BCL - 2 family. In addition, we have shown that downregulation of BCL - X-L using a BCL - X-L antisense oligonucleotide engenders mesothelioma apoptotic cell death in vitro and in vivo. The purpose of this study is to evaluate the efficacy of bcl2/bcl-x(L) inhibitor, 2 - methoxy antimycin A3, in inducing apoptosis and increasing chemo - sensitivity in vitro and in vivo. Several bcl-x(L) high - expression tumor cell lines and one normal human cell line were exposed to 2 - methoxy antimycin A3. 2 - methoxy antimycin A3 demonstrated significant growth inhibition only in these tumor cell lines, with little effect on normal human cells. Treatment with 2 - methoxy antimycin A3 alone resulted in a dramatic increase in the induction of apoptosis in the cancer cells. Apoptosis occurs through decreasing mitochondrial membrane potential and caspase activation. Notably, treatment with 2 - methoxy antimycin A3 does not alter BCL - 2 family protein expression. Synergistic inhibition of tumor growth by the coadministration of cisplatin and 2 - methoxy antimycin A3 was observed in both in vitro and in vivo experiments. Together, these findings indicate that exposure of cancer cells to small molecule Bcl-2/x(L) inhibitors such as 2 - methoxy antimycin A3 alone, or in the combination with other chemotherapeutics, may represent a novel therapeutic strategy in treatment of cancer, especially mesothelioma.