Cepharanthine hydrochloride reverses the mdr1 (P-glycoprotein)-mediated esophageal squamous cell carcinoma cell cisplatin resistance through JNK and p53 signals.

Guifeng Su,Suhong Chen,Hongyuan Chen,Hongce Chen,Yue Feng,Siyuan You,Ying Wang,Pengjun Zhou,Li Zhang,Huizhong Liu,Dandan Xu,Yifei Wang,Rong Zhang,Jinhong Qin,Wen Rui

doi:10.18632/oncotarget.22676

Abstract

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 in vitro and in vivo 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.

Highlights

RESULTSEsophageal cancer (EC) is the fourth most common cancer in China, with a total of 477,900 new cases and 375,000 deaths projected to occur in 2015 [1]
The inhibition of cell proliferation is associated with cell cycle, so we examined the effect of Cepharanthine hydrochloride (CEH) combined with cDDP on the cell cycle progression in Esophageal squamous cell carcinoma (ESCC) cells
We have previously demonstrated that CEH upregulated the expression of P53 and Jun N-terminal kinase (JNK), we used JNK inhibitor SP600125 or p53 inhibitor PFTα combined with CEH to determine the effects of CEH on the cDDPinduced expression of P-gp in Eca109 and Eca109/CDDP cells

Summary

Introduction

Esophageal cancer (EC) is the fourth most common cancer in China, with a total of 477,900 new cases and 375,000 deaths projected to occur in 2015 [1]. Esophageal squamous cell carcinoma (ESCC) is one of the main histological types of EC in China with diverse cancer risk profiles [2]. ESCC accounts for over 90% of esophageal cancer cases and 5-year survival rates over the past 30 years is less than 20% [3,4,5]. The clinical approach to ESCC is surgical treatment combined with radiotherapy and chemotherapy [6]. The most common treatment regimen for ESCC is the combination of cisplatin (cDDP) and 5-Fluorouracil (5-Fu) [7]. The obtained chemotherapy results were often barely satisfactory, mainly due to multiple drug resistance (MDR) [8, 9]

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