Role of glutathioneS-transferase P1, P-glycoprotein and multidrug resistance-associated protein 1 in acquired doxorubicin resistance

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Abstract
While P‐glycoprotein (Pgp) and multidrug resistance‐associated protein 1 (MRP1) are known to be important in acquired doxorubicin resistance, the role of glutathione S‐transferases (GST) remains unclear. Our study assessed roles of these 3 factors in a human drug‐sensitive carcinoma cell line (HEp2), a subclone made resistant by prolonged incubation in doxorubicin (HEp2A), and HEp2 cells stably transfected with human GSTP1. Drug‐resistant HEp2A cells showed greater total GST activity, GSTP class enzyme expression, Pgp expression, MRP1 transcript expression, drug efflux and at least 13‐fold greater resistance to doxorubicin than the parent HEp2 cell line. GSTM class enzyme expression was similar in both cell types, while GSTA class enzymes were not detected. In the resistant HEp2A cells, cytotoxicity was markedly enhanced by the Pgp/MRP inhibitor verapamil at low doxorubicin concentrations. The GST inhibitor curcumin also enhanced cytotoxicity in HEp2A cells when the Pgp/MRP efflux barrier had been reversed by verapamil or overcome by high doxorubicin concentrations. In addition, curcumin had a chemosensitising effect at low doxorubicin concentrations in HEp2 cells. Stable transfection of HEp2 cells with human GSTP1 increases doxorubicin resistance 3‐fold over control cells. Our study indicates involvement of GSTP enzymes as well as efflux mechanisms in the acquired doxorubicin‐resistance phenotype.