Preclinical studies of apogossypolone, a novel pan inhibitor of bcl-2 and mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells.
Preclinical studies of apogossypolone, a novel pan inhibitor of bcl-2 and mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells.
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DOI：
10.1097/mpa.0b013e3181bb95e7
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发表时间：
2010-04
期刊：
影响因子：
2.9
通讯作者：
Mohammad RM
中科院分区：
文献类型：
--
作者：
Banerjee S;Choi M;Aboukameel A;Wang Z;Mohammad M;Chen J;Yang D;Sarkar FH;Mohammad RM
抗凋亡Bcl-2家族蛋白的过表达使胰腺癌患者对常规治疗产生抵抗阿朴棉酚酮（ApoG 2）是（−）-棉酚的类似物，表现出结合活性，对Bcl-2的Ki值为35 nmol/L，对Mcl-1的Ki值为25 nmol/L。本研究旨在验证我们的假设，使用ApoG 2灭活Bcl-2家族蛋白是否可以使胰腺癌细胞对吉西他滨的细胞毒性作用敏感。采用MTT法和组蛋白/DNA酶联免疫吸附试验检测ApoG 2、吉西他滨及其联合作用对胰腺癌细胞株的细胞毒性和细胞凋亡的影响。进行免疫共沉淀实验以阐明ApoG 2的作用机制。在异种移植模型中评价ApoG 2的体内功效，以证实其与吉西他滨的治疗益处。当ApoG 2与吉西他滨组合时，细胞毒性和细胞凋亡明显增加。免疫共沉淀实验表明ApoG 2可阻断Mcl-1/Bax和Bcl-2/Bim的异源二聚化。此外，在重度联合免疫缺陷小鼠异种移植模型中，与ApoG 2或吉西他滨单独给药相比，ApoG 2与吉西他滨联合给药的抗肿瘤活性在统计学上更高。Apogossypolone作为一种有效的泛Bcl-2家族抑制剂，似乎对未来的翻译研究，包括胰腺癌的治疗有治疗前景。
Overexpression of antiapoptotic Bcl-2 family proteins confers resistance to conventional therapy in pancreatic cancer patients. Apogossypolone (ApoG2) is an analogue of (−)–gossypol, exhibiting binding activity with Ki values of 35 nmol/L for Bcl-2 and 25 nmol/L for Mcl-1. The present study was designed to test our hypothesis whether inactivation of Bcl-2 family of proteins using ApoG2 could sensitize pancreatic cancer cells to the cytotoxic effect of gemcitabine. Two pancreatic cancer cell lines were treated with ApoG2, gemcitabine, and their combination; cytotoxicity and apoptosis was confirmed by MTT and histone/DNA enzyme-linked immunosorbent assay. Coimmunoprecipitation experiments were performed to elucidate the mechanism of action of ApoG2. In vivo efficacy of ApoG2 was evaluated in a xenograft model to confirm its therapeutic benefit with gemcitabine. When ApoG2 was combined with gemcitabine, increased cytotoxicity and apoptosis was evident. Coimmunoprecipitation experiment revealed that ApoG2 blocks the heterodimerization of Mcl-1/Bax and Bcl-2/Bim in cells. Furthermore, administration of ApoG2 with gemcitabine resulted in a statistically higher antitumor activity compared with either ApoG2 or gemcitabine alone in a severe combined immunodeficiency mouse xenograft model. Apogossypolone, which functions as a potent pan–Bcl-2 family inhibitor, seems therapeutically promising for future translational studies including the treatment of pancreatic cancer.