Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700054, India.
Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700054, India; National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune 411007, Maharashtra, India.
J Biol Chem. 2011 Dec 9;286(49):42232-42247. doi: 10.1074/jbc.M111.262295. Epub 2011 Oct 19.
Breast cancer cells often develop multiple mechanisms of drug resistance during tumor progression, which is the major reason for the failure of breast cancer therapy. High constitutive activation of NFκB has been found in different cancers, creating an environment conducive for chemotherapeutic resistance. Here we report that doxorubicin-induced SMAR1-dependent transcriptional repression and SMAR1-independent degradation of IkBα resulted in nuclear translocation of p65NFκB and its association with p300 histone acetylase and subsequent transcription of Bcl-2 to impart protective response in drug-resistant cells. Consistently SMAR1-silenced drug-resistant cells exhibited IkBα-mediated inhibition of p65NFκB and induction of p53-dependent apoptosis. Interestingly, curcumin pretreatment of drug-resistant cells alleviated SMAR1-mediated p65NFκB activation and hence restored doxorubicin sensitivity. Under such anti-survival condition, induction of p53-p300 cross-talk enhanced the transcriptional activity of p53 and intrinsic death cascade. Importantly, promyelocyte leukemia-mediated SMAR1 sequestration that relieved the repression of apoptosis-inducing genes was indispensable for such chemo-sensitizing ability of curcumin. A simultaneous decrease in drug-induced systemic toxicity by curcumin might also have enhanced the efficacy of doxorubicin by improving the intrinsic defense machineries of the tumor-bearer. Overall, the findings of this preclinical study clearly demonstrate the effectiveness of curcumin to combat doxorubicin-resistance. We, therefore, suggest curcumin as a potent chemo-sensitizer to improve the therapeutic index of this widely used anti-cancer drug. Taken together, these results suggest that curcumin can be developed into an adjuvant chemotherapeutic drug.
乳腺癌细胞在肿瘤进展过程中常常会产生多种耐药机制，这是乳腺癌治疗失败的主要原因。在不同的癌症中，NFκB 的组成性激活已被发现，这为化疗耐药创造了有利的环境。在这里，我们报告阿霉素诱导的 SMAR1 依赖性转录抑制和 SMAR1 非依赖性 IκBα 降解导致 p65NFκB 核易位及其与 p300 组蛋白乙酰转移酶的结合，并随后转录 Bcl-2 以赋予耐药细胞保护性反应。一致地，沉默 SMAR1 的耐药细胞表现出 IκBα 介导的 p65NFκB 抑制和 p53 依赖性凋亡诱导。有趣的是，姜黄素预处理耐药细胞可减轻 SMAR1 介导的 p65NFκB 激活，并恢复阿霉素敏感性。在这种抗生存条件下，p53-p300 串扰的诱导增强了 p53 的转录活性和内在死亡级联。重要的是，早幼粒细胞白血病介导的 SMAR1 隔离对于姜黄素的这种化疗增敏作用是必不可少的，因为它解除了对凋亡诱导基因的抑制。姜黄素同时降低了药物引起的全身毒性，可能通过改善肿瘤携带者的内在防御机制，增强了阿霉素的疗效。总的来说，这项临床前研究的结果清楚地表明了姜黄素对抗阿霉素耐药的有效性。因此，我们建议将姜黄素作为一种有效的化疗增敏剂，以提高这种广泛使用的抗癌药物的治疗指数。综上所述，这些结果表明姜黄素可以开发为辅助化疗药物。
