Reversal of efflux of an anticancer drug in human drug-resistant breast cancer cells by inhibition of protein kinase Cα (PKCα) activity

Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine
Chan Woo KimYoshiki Katayama

Abstract

P-glycoprotein (Pgp) is a 170-kDa transmembrane protein that mediates the efflux of anticancer drugs from cells. Pgp overexpression has a distinct role in cells exhibiting multidrug resistance (MDR). We examined reversal of drug resistance in human MDR breast cancer cells by inhibition of protein kinase Cα (PKCα) activity, which is associated with Pgp-mediated efflux of anticancer drugs. PKCα activity was confirmed by measurement of phosphorylation levels of a PKCα-specific peptide substrate (FKKQGSFAKKK-NH2), showing relatively higher basal activity in drug-resistant MCF-7/ADR cells (84 %) than that in drug-sensitive MCF-7 cells (63 %). PKCα activity was effectively suppressed by the PKC inhibitor, Ro-31-7549, and reversal of intracellular accumulation of doxorubicin was observed by inhibition of PKCα activity in MCF-7/ADR cells compared with their intrinsic drug resistance. Importantly, increased accumulation of doxorubicin could enhance the therapeutic efficacy of doxorubicin in MDR cells significantly. These results suggest a potential for overcoming MDR via inhibition of PKCα activity with conventional anticancer drugs.

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Citations

Aug 16, 2016·Journal of Cancer Research and Clinical Oncology·Lauana Greicy Tonon LemosRaquel Ciuvalschi Maia
Apr 5, 2017·International Journal of Molecular Sciences·Abdullah MayatiOlivier Fardel
Jan 7, 2017·Oxidative Medicine and Cellular Longevity·Juan CenBian-Sheng Ji
Oct 24, 2018·Cancer Biomarkers : Section a of Disease Markers·Yi HuangJishi Wang
Jan 15, 2019·Cancer Cell International·Marta Llaurado FernandezMark S Carey
Jul 9, 2020·Apoptosis : an International Journal on Programmed Cell Death·Mehrdad GhashghaeiniaMartin Köberle

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