Cao Lixia, Zhao Shaorong, Yang Qianxi, Shi Zhendong, Liu Jingjing, Pan Teng, Zhou Dongdong, Zhang Jin
Third Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin, China.
Front Oncol. 2021 Mar 2;11:614458. doi: 10.3389/fonc.2021.614458. eCollection 2021.
The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aim to demonstrate the potential of chidamide (CHI) combined with the chemotherapy drug doxorubicin (DOX) to overcome chemotherapeutic resistance of breast cancer and , laying the experimental foundation for the next clinical application. The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells and compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 was activated in the CHI-treated group and combined treatment group, and then the activated p53 up-regulated p21, apoptosis regulator recombinant protein (Puma), and pro-apoptotic protein Bax, down-regulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis.
多药耐药（MDR）表型通常伴随着组蛋白脱乙酰酶（HDAC）的异常表达。鉴于HDAC在染色质重塑和表观遗传学中至关重要，抑制HDAC的作用已成为肿瘤治疗的重要方法。然而，HDAC抑制剂对MDR乳腺癌的作用尚未阐明。本研究旨在证明西达本胺（CHI）联合化疗药物阿霉素（DOX）克服乳腺癌化疗耐药性的潜力，为下一步临床应用奠定实验基础。结果表明，与CHI单药治疗相比，CHI联合DOX对MDR乳腺癌细胞具有显著的细胞毒性。细胞周期分布结果表明，无论是否添加DOX，CHI均导致G0/G1期细胞周期阻滞并抑制细胞生长。同时，膜联蛋白V染色和TUNEL染色结果表明，CHI增加了耐药细胞中的细胞凋亡数量。蛋白质免疫印迹分析发现，在CHI处理组和联合治疗组中p53被激活，然后激活的p53上调p21、凋亡调节重组蛋白（Puma）和促凋亡蛋白Bax，下调凋亡蛋白Bcl-xL和Bcl-2，并激活半胱天冬酶级联反应以诱导凋亡。
