Dissociation of the verapamil-induced enhancement of doxorubicin's cytotoxicity from changes in cellular accumulation or retention of doxorubicin in pancreatic cancer cell lines.
The poor response of pancreatic adenocarcinoma to conventional chemotherapy has prompted us to search for innovative treatment approaches. Verapamil, a calcium channel blocker, has been reported to increase the doxorubicin sensitivity of several tumor models with acquired resistance, often in association with decreased efflux resulting in increased net accumulation/retention of doxorubicin. The cell lines used in the present study, PANC-1 of human origin and two cell lines of hamster origin, WD PaCa and PD PaCa, exhibit primary or intrinsic doxorubicin resistance. Verapamil caused a dose-dependent enhancement of doxorubicin's cytotoxicity in the pancreatic cancer-cell lines studied. In PANC-1, WD PaCa, and PD PaCa, respectively, the enhancement was 10.4-, 281.01-, and 15.8-fold at 6.6 microM verapamil and 1.1-, 8.8-, and 6.3-fold at 1.0 microM verapamil. Of note is the finding that the verapamil enhancement of sensitivity to doxorubicin was most marked in our most drug resistant cell line (WD PaCa). However, minimal to no effect on the accumulation or retention of doxorubicin was documented. In addition, the intracellular metabolism of doxorubicin was not found to be altered by verapamil. The present study raises questions concerning the nature and mechanism(s) of primary anthracycline resistance.
Chang
B K
BK
Department of Medicine, Medical College of Georgia, Augusta.
Brenner
D E
DE
Gutman
R
R
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity*; D004357:Drug Synergism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000008:administration & dosage*
D004317:Doxorubicin; D014700:Verapamil