Zhou Pengjun, Zhang Rong, Wang Ying, Xu Dandan, Zhang Li, Qin Jinhong, Su Guifeng, Feng Yue, Chen Hongce, You Siyuan, Rui Wen, Liu Huizhong, Chen Suhong, Chen Hongyuan, Wang Yifei
Guangzhou Jinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, Guangdong, P. R. China.
Department of Pathogen Biology and Immunology, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, P. R. China.
Oncotarget. 2017 Nov 27;8(67):111144-111160. doi: 10.18632/oncotarget.22676. eCollection 2017 Dec 19.
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy that is often resistant to therapy. Nowadays, chemotherapy is still one of the main methods for the treatment of ESCC. However, the multidrug resistance (MDR)-mediated chemotherapy resistance is one of the leading causes of death. Exploring agents able to reverse MDR, which thereby increase the sensitivity with clinical first-line chemotherapy drugs, could significantly improve cancer treatment. Cepharanthine hydrochloride (CEH) has the ability to reverse the MDR in ESCC and the mechanism involved have not been reported. The aim of the study was to investigate the potential of CEH to sensitize chemotherapeutic drugs in ESCC and explore the underlying mechanisms by and studies. Our data demonstrated that CEH significantly inhibited ESCC cell proliferation in a dose-dependent manner, induced G2/M phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to cisplatin (cDDP). Mechanistically, CEH inhibited ESCC cell growth and induced apoptosis through activation of c-Jun, thereby inhibiting the expression of P-gp, and enhancing p21 expression via activation of the p53 signaling pathway. In this study, we observed that growth of xenograft tumors derived from ESCC cell lines in nude mice was also significantly inhibited by combination therapy. To our knowledge, we demonstrate for the first time that CEH is a potentially effective MDR reversal agent for ESCC, based on downregulation of the mRNA expression of MDR1 and P-gp. Together, these results reveal emphasize CEH putative role as a resistance reversal agent for ESCC.
食管鳞状细胞癌（ESCC）是一种侵袭性恶性肿瘤，通常对治疗具有抗性。如今，化疗仍是ESCC治疗的主要方法之一。然而，多药耐药（MDR）介导的化疗耐药是主要死亡原因之一。探索能够逆转MDR从而增加对临床一线化疗药物敏感性的药物，可显著改善癌症治疗。盐酸千金藤素（CEH）具有逆转ESCC中MDR的能力，但其涉及的机制尚未见报道。本研究的目的是通过[具体实验方法1]和[具体实验方法2]研究，探讨CEH使ESCC对化疗药物敏感的潜力，并探索其潜在机制。我们的数据表明，CEH以剂量依赖性方式显著抑制ESCC细胞增殖，诱导G2/M期细胞周期阻滞和凋亡，并增加对顺铂（cDDP）耐药的细胞系的敏感性。机制上，CEH通过激活c-Jun抑制ESCC细胞生长并诱导凋亡，从而抑制P-糖蛋白（P-gp）的表达，并通过激活p53信号通路增强p21表达。在本研究中，我们观察到联合治疗也显著抑制了裸鼠体内源自ESCC细胞系的异种移植肿瘤的生长。据我们所知，基于MDR1和P-gp mRNA表达的下调，我们首次证明CEH是一种对ESCC潜在有效的MDR逆转剂。总之，这些结果强调了CEH作为ESCC耐药逆转剂的假定作用。
