title: Increase in doxorubicin cytotoxicity by carvedilol inhibition of P-glycoprotein activity.
abstract: 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 micromol/L), and even more markedly, carvedilol (10 micromol/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 micromol/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 micromol/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.
authors.affiliation: Department of Clinical Chemistry, Umeå University, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Jonsson
authors.forename: P
authors.initials: P
authors.lastname: Behnam-Motlagh
authors.forename: M
authors.initials: M
authors.lastname: Persson
authors.forename: R
authors.initials: R
authors.lastname: Henriksson
authors.forename: K
authors.initials: K
authors.lastname: Grankvist
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005452:Fluoresceins / Q000378:metabolism; D005453:Fluorescence; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D011412:Propanolamines / Q000494:pharmacology*; D011748:Pyrogallol / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002227:Carbazoles; D005452:Fluoresceins; D005609:Free Radicals; D011412:Propanolamines; D011748:Pyrogallol; D000077261:Carvedilol; D004317:Doxorubicin; D014700:Verapamil; C007740:fluorexon