Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells
Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells
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DOI：
10.1158/1078-0432.ccr-04-0361
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发表时间：
2004-10-15
影响因子：
11.5
通讯作者：
Meric-Bernstam, F
中科院分区：
文献类型：
--
作者：
Mondesire, WH;Jian, WG;Meric-Bernstam, F
目的：雷帕霉素的丝氨酸-苏氨酸激酶已成为肿瘤治疗的潜在靶点。雷帕霉素和雷帕霉素类似物正在进行临床试验，并已在一组患者中诱导临床反应。据报道，雷帕霉素还可以增强几种细胞毒剂的疗效。本研究的目的是确定雷帕霉素与作为乳腺癌一线和二线药物的化疗药物之间的相互作用的性质。实验设计：我们在体外对雷帕霉素敏感和耐药的细胞进行了多药效应/联合指数等谱分析，并在雷帕霉素敏感的模型中评估了联合治疗的体内疗效。结果：在体外，紫杉醇、卡铂和长春瑞滨联合作用观察到协同作用。阿霉素和吉西他滨联合应用时可观察到相加效应。雷帕霉素显著增强紫杉醇和卡铂诱导的细胞凋亡。这种作用是序列依赖的，至少部分是通过caspase激活来调节的。此外，雷帕霉素提高了HER2/neu过表达细胞对紫杉醇和卡铂的化疗敏感性，提示了一种治疗这些行为不良的肿瘤的潜在方法。对雷帕霉素的生长抑制作用耐药的细胞株也对雷帕霉素介导的化疗增敏作用耐药。在体内，雷帕霉素联合紫杉醇可显著缩小雷帕霉素敏感肿瘤的肿瘤体积。结论：在对雷帕霉素敏感的细胞系中，由于磷脂酰肌醇3‘-激酶/Akt通路的异常，雷帕霉素增强了所选化疗药物的细胞毒作用，提示联合治疗可能对因该通路异常而被选中的患者有效。
Purpose: The serine-threonine kinase mammalian target of rapamycin has emerged as a potential target for cancer therapy. Rapamycin and rapamycin analogs are undergoing clinical trials and have induced clinical responses in a subgroup of patients. Rapamycin has also been reported to enhance the efficacy of several cytotoxic agents. The aim of this study was to determine the nature of the interactions between rapamycin and chemotherapeutic agents used as first- and second-line agents against breast cancer.Experimental Design: We performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model.Results: In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel- and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu-overexpressing cells, suggesting a potential approach to these poorly behaving tumors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in tumor volume compared with either agent alone in rapamycin-sensitive tumors.Conclusions: Rapamycin potentiates the cytotoxicity of selected chemotherapeutic agents in cell lines sensitive to the effects of rapamycin due to aberrations in the phosphatidylinositol 3'-kinase/Akt pathway, suggesting that combination therapy may be effective in patients selected for aberrations in this pathway.