Enhancing the antiproliferative effect of topoisomerase II inhibitors using a polypeptide inhibitor of c-Myc
Enhancing the antiproliferative effect of topoisomerase II inhibitors using a polypeptide inhibitor of c-Myc
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DOI：
10.1016/j.bcp.2005.10.041
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发表时间：
2006-01-12
影响因子：
5.8
通讯作者：
Raucher, D
中科院分区：
文献类型：
--
作者：
Bidwell, GL;Raucher, D
拓扑异构酶II抑制剂广泛用于癌症化疗。然而，它们的使用受到对正常组织的严重副作用（包括心脏毒性）的限制。降低正常组织细胞毒性的一种方法可能是使癌细胞对这些药物的毒性敏感，从而允许以更低且更安全的剂量施用它们。许多类型癌症的一个标志是 c-Myc 的过度表达，而针对 c-Myc 的分子对癌细胞的影响将比对正常组织的影响更显着。该报告表明，用抑制 c-Myc 转录功能的息肉对细胞进行预处理，会导致细胞对拓扑异构酶 II 抑制剂阿霉素和依托泊苷更敏感。这种多肽对 c-Myc 和 Max 二聚化的抑制导致在测试的三种不同细胞系中阿霉素和依托泊苷的 IC50 降低多达 2 倍。此外，c-Myc 抑制剂通过增强阿霉素和依托泊苷诱导的 GO/Gj 积累来影响 MCF-7 乳腺癌细胞的细胞周期分布。我们已经证明，这种效应并不是由于药物蓄积增强或药物流出抑制所致。相反，这可能是由于 c-Myc 抑制的转录后果，特别是多胺合成酶鸟氨酸脱羧酶水平的降低。总之，我们的结果表明，抑制 c-Myc 转录功能的多肽可能被证明是与拓扑异构酶 II 抑制药物联合治疗的有用工具。 (c) 2005 Elsevier Inc. 保留所有权利。
Topoisomerase II inhibitors are widely used in cancer chemotherapy. However, their use is limited by severe adverse effects to normal tissues, including cardiotoxicity. One approach to reduce the cytotoxicity in normal tissues may be to sensitize cancer cells to the toxicity of these agents, allowing them to be administered in a lower and safer dose. A hallmark of many types of cancer is overexpression of c-Myc, and a molecule which targets c-Myc will affect the cancer cells more significantly than the normal tissues. This report demonstrates that pretreatment of cells with a polypepticle, which inhibits c-Myc transcriptional function causes cells to be more susceptible to the topoisomerase II inhibitors doxorubicin and etoposide. Inhibition of c-Myc and Max dimerization by this polypepticle leads to as much as a 2-fold reduction in the doxorubicin and etoposide IC50 in three different cell lines tested. Furthermore, the c-Myc inhibitor affects the cell cycle distribution of MCF-7 breast cancer cells by enhancing the GO/Gj accumulation induced by doxorubicin and etoposide. We have shown that this effect is not due to enhanced drug accumulation or inhibited drug efflux. Rather, it is likely due to the transcriptional consequences of c-Myc inhibition, specifically reduction in the levels of the polyamine synthesizing enzyme ornithine decarboxylase. in summary, our results suggest that polypeptides, which inhibit c-Myc transcriptional function, may prove to be a useful tool in combination therapy with topoisomerase II inhibiting drugs. (c) 2005 Elsevier Inc. All rights reserved.