Potentiation of some anticancer agents by dipyridamole against drug-sensitive and drug-resistant cancer cell lines.
In this study, we have used two different vincristine (VCR)-resistant variants, VJ-300 and HC-7-5/VCR. VJ-300 was isolated from a human cancer KB cell line and HC-7-5/VCR from a human cancer HC-7-5 cell line. VJ-300 and HC-7-5/VCR are both multidrug-resistant (MDR) variants, showing resistance to multiple anticancer drugs such as VCR, adriamycin, actinomycin D and daunomycin. Dipyridamole, a specific inhibitor of nucleoside transport, potentiated these anticancer drugs about 2- to 10-fold against KB and VJ-300. Dipyridamole almost completely reversed drug resistance to actinomycin D in VJ-300 cells with about a 70-fold higher resistance to actinomycin D. Dipyridamole inhibited the efflux of actinomycin D and VCR from VJ-300 cells. Dipyridamole enhanced the uptake of VCR but not that of actinomycin D in VJ-300 and KB. Dipyridamole at 10-100 microM inhibited photoaffinity labeling with [3H]azidopine of the cell-surface protein P-glycoprotein in VJ-300 cells. Dipyridamole potentiated 5-fluorouracil and hexylcarbamoyl-5-fluorouracil in cultured KB and VJ-300, but it annihilated the cytotoxic action of 5-fluorouridine. Potentiation of 5-fluorouracil by dipyridamole against HC-7-5 and HC-7-5/VCR was also observed, but appeared to be less than in VJ-300 and KB cells. Dipyridamole almost completely inhibited the cellular accumulation of 5-fluorouridine, but not that of 5-fluorouracil. Thus, dipyridamole appeared to potentiate anticancer agents through pleiotropic action sites, one of which is inhibition of enhanced efflux of MDR cell lines and the other of which is inhibition of nucleoside transport. Dipyridamole might be a useful and potent agent to potentiate anticancer agents and reverse drug-resistance.
Asoh
K
K
Department of Biochemistry, Oita Medical School.
Saburi
Y
Y
Sato
S
S
Nogae
I
I
Kohno
K
K
Kuwano
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001386:Azides; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D004095:Dihydropyridines; D004176:Dipyridamole / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; D003609:Dactinomycin; D014750:Vincristine; C041130:azidopine; D004176:Dipyridamole; D005472:Fluorouracil