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

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 inducing toxic hyperactivation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR). BHPI increased sensitivity of MDR1 overexpressing multidrug resistant OVCAR-3 ovarian cancer cells to killing by paclitaxel by >1,000 fold. BHPI also restored doxorubicin sens

SUBMITTER: Zheng X 

PROVIDER: S-EPMC5871075 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature