Tissue and Cell Culture Unit (TCCU), CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow, India.
PLoS One. 2012;7(6):e37736. doi: 10.1371/journal.pone.0037736. Epub 2012 Jun 29.
Polyphenols as "sensitizers" together with cytotoxic drugs as "inducers" cooperate to trigger apoptosis in various cancer cells. Hence, their combination having similar mode of mechanism may be a novel approach to enhance the efficacy of inducers. Additionally, this will also enable to achieve the physiological concentrations facilitating significant increase in the activity at concentrations which the compound can individually provide. Here we propose that polyphenols (Resveratrol (RES) and Curcumin (CUR)) pre-treatment may sensitize MCF-7/MDA MB-231 (Human Breast Cancer Cells, HBCCs) to Centchroman (CC, antineoplastic agent). 6 h pre-treated cells with 10 µM RES/CUR and 100 µM RES/30 µM CUR doses, followed by 10 µM CC for 18 h were investigated for Ser-167 ER-phosphorylation, cell cycle arrest, redox homeostasis, stress activated protein kinase (SAPKs: JNK and p38 MAPK) pathways and downstream apoptosis effectors. Low dose RES/CUR enhances the CC action through ROS mediated JNK/p38 as well as mitochondrial pathway in MCF-7 cells. However, RES/CUR sensitization enhanced apoptosis in p53 mutant MDA MB-231 cells without/with involvement of ROS mediated JNK/p38 adjunct to Caspase-9. Contrarily, through high dose sensitization in CC treated cells, the parameters remained unaltered as in polyphenols alone. We conclude that differential sensitization of HBCCs with low dose polyphenol augments apoptotic efficacy of CC. This may offer a novel approach to achieve enhanced action of CC with concomitant reduction of side effects enabling improved management of hormone-dependent breast cancer.
多酚类化合物作为“敏化剂”，细胞毒性药物作为“诱导剂”，共同作用于各种癌细胞，触发细胞凋亡。因此，它们具有相似作用机制的联合使用可能是提高诱导剂疗效的一种新方法。此外，这也将使我们能够实现生理浓度，从而在化合物单独提供的浓度下显著增加其活性。在这里，我们提出多酚类化合物（白藜芦醇（RES）和姜黄素（CUR））预处理可能使 MCF-7/MDA MB-231（人乳腺癌细胞，HBCCs）对 Centchroman（CC，抗肿瘤剂）敏感。用 10µM RES/CUR 和 100µM RES/30µM CUR 剂量预处理 6 小时的细胞，然后用 10µM CC 处理 18 小时，研究 Ser-167 ER 磷酸化、细胞周期停滞、氧化还原稳态、应激激活蛋白激酶（SAPKs：JNK 和 p38 MAPK）途径和下游凋亡效应子。低剂量 RES/CUR 通过 ROS 介导的 JNK/p38 以及 MCF-7 细胞中线粒体途径增强 CC 的作用。然而，RES/CUR 敏化作用增强了 p53 突变 MDA MB-231 细胞中的凋亡，而不涉及 ROS 介导的 JNK/p38 以及 Caspase-9。相反，在 CC 处理细胞中通过高剂量敏化，参数保持不变，与单独使用多酚类化合物时相同。我们得出结论，低剂量多酚类化合物对 HBCCs 的差异敏化增强了 CC 的凋亡功效。这可能提供一种新方法，以增强 CC 的作用，同时减少副作用，从而改善激素依赖性乳腺癌的管理。
