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

摘要

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 C alpha (PKC alpha) activity, which is associated with Pgp-mediated efflux of anticancer drugs. PKC alpha activity was confirmed by measurement of phosphorylation levels of a PKC alpha-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 %). PKC alpha activity was effectively suppressed by the PKC inhibitor, Ro-31-7549, and reversal of intracellular accumulation of doxorubicin was observed by inhibition of PKC alpha 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 PKC alpha activity with conventional anticancer drugs.