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

被引:55
|
作者
Jonsson, O
Behnam-Motlagh, P
Persson, M
Henriksson, R
Grankvist, K
机构
[1] Umea Univ, Dept Clin Chem, S-90187 Umea, Sweden
[2] Umea Univ, Dept Oncol, S-90187 Umea, Sweden
关键词
carvedilol; doxorubicin; MDR; vasoactive drugs; P-glycoprotein; verapamil;
D O I
10.1016/S0006-2952(99)00262-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Acquired resistance to chemotherapy is a major problem during cancer treatment. One mechanism for drug resistance is overexpression of the MDR1 (multidrug resistance) gene encoding for the transmembrane efflux pump, P-glycoprotein (P-gp). The calcium channel blocker verapamil has been shown to reverse cellular drug resistance by inhibiting P-gp drug efflux. This study evaluated whether the new antihypertensive drug carvedilol influenced doxorubicin (Dox) cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. Verapamil (10 mu mol/L), and even more markedly, carvedilol (10 mu mol/L) increased cellular uptake of P-gp transported calcein of a P-gp-expressing breast cancer cell line (Hs578T-Dox). In the subline (Hs578T) not expressing P-gp, no effects of carvedilol or verapamil on calcein uptake were seen. Carvedilol and verapamil (10 mu mol/L) reduced 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 the LD50 of the Hs578T subline was only marginally affected. Carvedilol (10 mu mol/L) reduced P-gp activity approximately twice as effectively as verapamil at an equimolar concentration. Carvedilol did not affect pyrogallol cytotoxicity and pyrogallol was without effect on calcein accumulation of the Hs578T-Dox cell line, indicating the lack of antioxidative properties affecting 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.
引用
收藏
页码:1801 / 1806
页数:6
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