Targeting multidrug-resistant ovarian cancer through estrogen receptor α dependent ATP depletion caused by hyperactivation of the unfolded protein response

作者：Xiaobin Zheng, Neal Andruska, Michael J. Lambrecht, Sisi He, Amadeo M. Parissenti, Paul J. Hergenrother, Erik R. Nelson, David J. Shapiro · 发表于：Oncotarget · 年份：2016 · DOI：10.18632/oncotarget.10819 · 被引用次数：32 · 研究领域：Drug Transport and Resistance Mechanisms、Endoplasmic Reticulum Stress and Disease、RNA Interference and Gene Delivery

// Xiaobin Zheng 1 , Neal Andruska 1,6 , Michael J. Lambrecht 2 , Sisi He 3 , Amadeo Parissenti 4 , Paul J. Hergenrother 2 , Erik R. Nelson 3,5 and David J. Shapiro 1,5,6 1 Department of Biochemistry University of Illinois, Urbana, IL, USA 2 Department of Chemistry, University of Illinois, Urbana, IL, USA 3 Department of Molecular Integrative Physiology, University of Illinois, Urbana, IL, USA 4 Cancer Research Program, Advanced Medical Research Institute of Canada, Sudbury, ON, Canada 5 University of Illinois Cancer Center, Urbana, IL, USA 6 College of Medicine, University of Illinois, Urbana, IL, USA Correspondence to: David J. Shapiro, email: // Keywords : ERα biomodulator; ATP depletion; unfolded protein response (UPR); MDR1/P-glycoprotein/ABCB1; OVCAR-3 ovarian cancer Received : May 02, 2016     Accepted : July 10, 2016     Epub: July 24, 2016     Published: March 13, 2018 Abstract Ovarian cancers often recur and tumors acquire resistance to chemotherapy due to overexpression of the ATP-dependent efflux pump, multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1). Nontoxic small molecule inhibitors targeting MDR1 have remained largely elusive. Instead, in a novel application of our recently described estrogen receptor α (ERα) biomodulator, BHPI, we targeted MDR1’s substrate, ATP. BHPI depletes intracellular ATP and nearly blocks MDR1-mediated drug efflux in ovarian cancer cells by ind...