MiR-495 sensitizes MDR cancer cells to the combination of doxorubicin and taxol by inhibiting MDR1 expression.

Zhenyou Zou,Chenmin Zhao,Chaoqun Chen,Daoquan Fang,Yao Lu,Zhi Chen,Xueyin Ni,Shuangshuang Lu,Jingsang Hu,Jinyao Chen,Chenyang Qiu,Ruyi Zou,Yanyuan Dong,Jie Huang,Jing Cai,Zhihe Zhong,Dan Zong,Weihao Liu,Yuan Liu,Jiahui Zhu,Xiaojie Lao,Qisha Qiu,Wenhui Huang,Xiaoli Huang,Dengqiang Wu,Yonghong Shi,Liguan Chen,Yuya Wu,Xiaoyan Bao,Yong Liang,Yujie Su ,Meiyan Jiang

doi:10.1111/jcmm.13114

Abstract

MDR1 is highly expressed in MDR A2780DX5 ovarian cancer cells, MDR SGC7901R gastric cancer cells and recurrent tumours. It pumps cytoplasmic agents out of cells, leading to decreased drug accumulation in cells and making cancer cells susceptible to multidrug resistance. Here, we identified that miR‐495 was predicted to target ABCB1, which encodes protein MDR1. To reduce the drug efflux and reverse MDR in cancer cells, we overexpressed a miR‐495 mimic in SGC7901R and A2780DX cells and in transplanted MDR ovarian tumours in vivo. The results indicated that the expression of MDR1 in the above cells or tumours was suppressed and that subsequently the drug accumulation in the MDR cells was decreased, cell death was increased, and tumour growth was inhibited after treatment with taxol‐doxorubicin, demonstrating increased drug sensitivity. This study suggests that pre‐treatment with miR‐495 before chemotherapy could improve the curative effect on MDR1‐based MDR cancer.

Highlights

Cancer is responsible for millions of deaths each year [1]
In the low MDR1-expressing cells, we examined the increase in drug resistance after MDR1 enhancement
multidrug resistance (MDR) cells can tolerate a high dosage of combination drug treatment and express high levels of MDR1

Summary

Introduction

Cancer is responsible for millions of deaths each year [1]. Chemotherapy is the most commonly adopted method to treat this devastating disease, but the development of multidrug resistance (MDR) can protect malignant cells from drugs, thereby greatly weakening the efficiency of the treatment [2].Enzymes, anti-apoptotic genes and DNA repair mechanisms reportedly contribute to MDR [3, 4]. Chemotherapy is the most commonly adopted method to treat this devastating disease, but the development of multidrug resistance (MDR) can protect malignant cells from drugs, thereby greatly weakening the efficiency of the treatment [2]. P-gp, named MDR protein 1 (MDR1, a membrane-associated protein encoded by the ABCB1 gene), can remove intracellular drugs from cells. The overexpression of MDR1 decreases drug accumulation and makes cells susceptible to MDR. For these reasons, several therapies have been focused on the inhibition of ABCB1. Three generations of MDR1 inhibitors have been developed since 1981, when Tsuruo et al found that the MDR of vincristine-resistant P388/VCR leukaemia cells

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