Resistance to anthrapyrazoles and anthracyclines in multidrug-resistant P388 murine leukemia cells: reversal by calcium blockers and calmodulin antagonists

A series of anthrapyrazoles was examined for their cytotoxic effect on P388 cells resistant (P388R) to anthracyclines, N-[4-(9-acridinylamino)-3-methoxyphenyl] methanesulfonamide, trimetrexate, and vinblastine. The degree of resistance of P388R cells to Adriamycin (ADR) and daunomycin was 50-fold and 38-fold, respectively, when compared to the parent cell line (P388S). The Adriamycin-resistant cells were highly cross-resistant to some anthrapyrazoles, but the degree of cross-resistance was not uniform and was less than 3-fold for one member of the series. The lipophilicity of these compounds appeared to correlate to some extent with the level of resistance. The calcium channel blockers verapamil (VER) and diltiazem and the calmodulin antagonist trifluoperazine potentiated the cytotoxicity of the anthrapyrazoles and ADR in P388R. This potentiating effect was concentration dependent with VER being the most efficacious. VER increased ADR cytotoxicity by greater than 10-fold and CI-937 by almost 40-fold. However, VER, diltiazem, and trifluoperazine had no effect on ADR or anthrapyrazole activity in P388S cells. The antiarrhythmic drug, quinidine, and the detergent, Tween 80, also potentiated ADR activity in P388R cells to the same extent as VER. Both the net accumulation and efflux of [3H]daunomycin were altered in P388R cells by nontoxic concentrations of Tween 80 in a fashion virtually identical to that demonstrated for VER. These data suggest that agents which potentiate drug cytotoxicity in P388R cells may do so by their interaction with the lipid domain of the plasma membrane. In addition, these results demonstrate that some members of the new series of DNA binding drugs, the anthrapyrazoles, may be active against anthracycline-resistant tumors and that, where cross-resistance to them occurs, it can be partially reversed by agents such as VER.