PDF(Pubmed)
Abstract：
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks an actionable target with limited treatment options beyond conventional chemotherapy. Therapeutic failure is often encountered due to inherent or acquired resistance to chemotherapy. Previous studies implicated PI3K/Akt/mTOR signaling pathway in cancer stem cells (CSCs) enrichment and hence chemoresistance. The present study aimed at investigating the potential effect of piperine (PIP), an amide alkaloid isolated from Piper nigrum, on enhancing the sensitivity of TNBC cells to doxorubicin (DOX) in vitro on MDA-MB-231 cell line and in vivo in an animal model of Ehrlich ascites carcinoma solid tumor. Results showed a synergistic interaction between DOX and PIP on MDA-MB-231 cells. In addition, the combination elicited enhanced suppression of PI3K/Akt/mTOR signaling that paralleled an upregulation in this pathway\'s negative regulator, PTEN, along with a curtailment in the levels of the CSCs surrogate marker, aldehyde dehydrogenase-1 (ALDH-1). Meanwhile, in vivo investigations demonstrated the potential of the combination regimen to enhance necrosis while downregulating PTEN and curbing PI3K levels as well as p-Akt, mTOR, and ALDH-1 immunoreactivities. Notably, the combination failed to change cleaved poly-ADP ribose polymerase levels suggesting a pro-necrotic rather than pro-apoptotic mechanism. Overall, these findings suggest a potential role of PIP in decreasing the resistance to DOX in vitro and in vivo, likely by interfering with the PI3K/Akt/mTOR pathway and CSCs.
摘要：
三阴性乳腺癌（TNBC）是乳腺癌的一种侵袭性亚型，缺乏可行的靶标，除了常规化疗之外，治疗选择有限。由于对化疗的固有或获得性抗性,经常遇到治疗失败。先前的研究暗示PI3K/Akt/mTOR信号通路在癌症干细胞(CSC)富集和因此的化学抗性中。本研究旨在研究胡椒碱（PIP）的潜在作用，一种从黑胡椒中分离出的酰胺生物碱，在MDA-MB-231细胞系上和在Ehrlich腹水癌实体瘤动物模型中体内增强TNBC细胞对多柔比星（DOX）的敏感性。结果显示在MDA-MB-231细胞上DOX和PIP之间的协同相互作用。此外,该组合引起PI3K/Akt/mTOR信号传导的抑制增强，与该途径的负调节因子的上调平行，PTEN,随着CSC替代标志物水平的削减，醛脱氢酶-1(ALDH-1)。同时,体内研究表明，联合治疗方案可增强坏死，同时下调PTEN和抑制PI3K水平以及p-Akt，mTOR,和ALDH-1免疫反应性。值得注意的是,该组合未能改变裂解的聚ADP核糖聚合酶水平,提示存在促坏死而非促凋亡机制.总的来说,这些发现表明PIP在体外和体内降低对DOX的抗性方面的潜在作用，可能是通过干扰PI3K/Akt/mTOR通路和CSC。
