Increase in doxorubicin cytotoxicity by carvedilol inhibition of P-glycoprotein activity

Acquired resistance to chemotherapy is a major problem during cancer treatm ent. One mechanism for drug resistance is overexpression of the MDR1 (multi drug resistance) gene encoding for the transmembrane efflux pump, P-glycopr otein (P-gp). The calcium channel blocker verapamil has been shown to rever se cellular drug resistance by inhibiting P-gp drug efflux. This study eval uated whether the new antihypertensive drug carvedilol influenced doxorubic in (Dox) cytotoxicity and P-gp activity in a P-gp-expressing cell line comp ared to a non-expressing subline. Verapamil (10 mu mol/L), and even more ma rkedly, carvedilol (10 mu mol/L) increased cellular uptake of P-gp transpor ted calcein of a P-gp-expressing breast cancer cell line (Hs578T-Dox). In t he subline (Hs578T) not expressing P-gp, no effects of carvedilol or verapa mil on calcein uptake were seen. Carvedilol and verapamil (10 mu mol/L) red uced the LD50 (dose which results in the death of half the number of cells) of the Hs578T-Dox subline from 200 mg/L to approx. 10 mg/L Dox, whereas th e LD50 of the Hs578T subline was only marginally affected. Carvedilol (10 m u mol/L) reduced P-gp activity approximately twice as effectively as verapa mil at an equimolar concentration. Carvedilol did not affect pyrogallol cyt otoxicity and pyrogallol was without effect on calcein accumulation of the Hs578T-Dox cell line, indicating the lack of antioxidative properties affec ting P-gp activity and associated toxicity of the drug. The results suggest that carvedilol has the clinical potential to reverse tumour MDR involving the efflux protein P-gp. BIOCHEM PHARMACOL 58;11:1801-1806, 1999. (C) 1999 Elsevier Science Inc.