Factors governing the modulation of vinca-alkaloid resistance in doxorubicin-resistant cells by the calmodulin inhibitor trifluoperazine.
Calmodulin inhibitors enhance the cytotoxic effects of doxorubicin (DOX) in DOX-resistant (P388/DOX) P388 mouse leukemia cells by augmenting cellular accumulation and retention of drug. In P388/DOX cells which are cross-resistant to vinblastine (VLB) and vincristine (VCR), cell kill following treatment with VLB and VCR alone was evident only after 12 hr of treatment. Additionally, the 2- to 10-fold increase in cytotoxicity of the vinca alkaloids in the presence of 2 and 4 microM trifluoperazine (TFP) was observed only in P388/DOX cells treated for 12 hr, but not for 3 or 6 hr. However, in DOX-sensitive (P388/S) P388 mouse leukemia cells, cytotoxic effects of VCR but not VLB were apparent after treatment for 3 hr, and cell kill with VLB and VCR was enhanced 2- to 20-fold in the presence of 2 and 4 microM TFP following treatment for 12 hr. Cellular accumulation of [3H]VLB in P388/DOX cells was 12-fold lower than in similarly treated P388/S cells and, in the presence of 2 and 4 microM TFP, cellular VLB levels were enhanced 1.3- to 2.0-fold in P388/S cells and 2- to 8-fold in P388/DOX cells. The effect of TFP in increasing cellular retention of [3H]VLB was more apparent with P388/DOX cells, and retention of [3H]VLB in the presence of 4 microM TFP was enhanced less than 1.5-fold and greater than 4-fold in P388/S and P388/DOX cells respectively. Results from this study and our earlier observations with DOX and TFP in P388/DOX cells demonstrate that: (1) TFP potentiates the cytotoxicity of VLB and VCR in P388/S and P388/DOX cells by augmenting drug accumulation and retention; (2) enhanced cell kill in the presence of TFP with P388/DOX cells is apparent at 1 hr for DOX vs 12 hr for VLB and VCR; and (3) in P388/S cells, TFP has a more striking effect on the cellular accumulation, retention and cytotoxicity of VLB and VCR rather than DOX.
D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D014268:Trifluoperazine / Q000494:pharmacology*; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014750:Vincristine / Q000378:metabolism / Q000494:pharmacology
D002147:Calmodulin; D014748:Vinca Alkaloids; D014268:Trifluoperazine; D014750:Vincristine; D014747:Vinblastine; D004317:Doxorubicin