title: Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by perhexiline maleate.
abstract: The effects of perhexiline maleate on growth and drug sensitivity were studied in the P388 murine leukemia cell line and in an anthracycline-resistant subline (P388/ADR). At noninhibitory concentrations, perhexiline maleate markedly increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on anthracycline-sensitive cells. The effects of perhexiline maleate on P388/ADR cells were reversible. Perhexiline maleate also increased the accumulation of another anthracycline, daunorubicin, in P388/ADR cells but did not increase its accumulation in the anthracycline-sensitive cells. Perhexiline maleate did not affect the sensitivity of either cell line to methotrexate or to 6-mercaptopurine. However, its effects on the sensitivity and on drug accumulation of vinblastine, a drug to which P388/ADR cells are cross-resistant, were similar to those observed for the anthracyclines. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not suggest that this mechanism is involved in its enhancement of the sensitivity of P388/ADR cells to doxorubicin. We suggest instead that this effect might be associated with alterations of cell lipid metabolism induced by perhexiline maleate.
mesh_terms: D000818:Animals; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D004351:Drug Resistance; D007700:Kinetics; D007941:Leukemia P388 / Q000503:physiopathology*; D007942:Leukemia, Experimental / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D010480:Perhexiline / Q000031:analogs & derivatives* / Q000633:toxicity; D014747:Vinblastine / Q000633:toxicity
chemical_list: D014747:Vinblastine; D004317:Doxorubicin; C023470:perhexiline maleate; D010480:Perhexiline; D003630:Daunorubicin