Journal of Chinese Pharmaceutical Sciences ›› 2015, Vol. 24 ›› Issue (5): 273-284.DOI: 10.5246/jcps.2015.05.036

• Review •     Next Articles

Reversal of multidrug resistance in cancer treatment by regulating multidrug resistance gene1: focus on nuclear receptors and epigenetics

Tingting Li1,2, Zhijun Wang3, Haiyan Liu2, Huiru Xie1, Xuehua Jiang1, Ling Wang1*   

  1. 1. West China School of Pharmacy, Sichuan University, Chengdu 610065, China
    2. Pharmacy Department of People's Hospital of Xishuangbanna Dai Autonomous Prefecture, Jinghong 666100, China
    3. Center for Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona CA 91766, US
  • Received:2014-12-08 Revised:2015-01-28 Online:2015-05-20 Published:2015-02-26
  • Contact: Tel.: 86-28-85503968, Fax: 86-28-85503024


Overexpression of P-glycoprotein (P-gp) encoded by the multidrug resistance gene-1 (MDR-1) is the main mechanism responsible for multidrug resistance (MDR) in a majority of cancer cells. However, the mechanism by which cancer cells acquire high levels of P-gp has not been well defined. Accumulating evidence suggests that nuclear receptors (NRs), especially human pregnane X receptor (PXR), play a crucial role in multidrug resistance. It has been shown that chemotherapeutic drug activates PXR and then enhances P-gp expression. Genetic knockdown or pharmacologic inhibition of PXR led to attenuation of drug-inducedMDR1 over expression, implying that NRs may be an effective target to reverse multidrug resistance. Recent investigations suggested that transcriptional activity of NRs is mediated by methylases, the important enzymes involved in epigenetic regulation. Other epigenetic modifications, such as promoter methylation, histone deacetylases and microRNAs, were also found to be involved in activation of MDR1 promoter, though the underlying mechanisms are not thoroughly known. In this review, we summarized recent researches in the regulation of P-gp expression, with particular focus on NRs and epigenetics, aiming to provide references and options to reverse and/or prevent MDR in cancer treatment.

Key words: Multidrug resistance, P-glycoprotein, Nuclear receptors, Epigenetics

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