perhexiline-maleate and Leukemia-P388

Acquired resistance to doxorubicin in a P388 murine leukemia cell subline was found to be associated with decreased drug accumulation in these cells. We have previously shown that the lipid domain of the plasma membrane in drug-resistant cells is structurally more ordered and has a lower phosphatidylcholine/sphingomyelin ratio. Perhexiline maleate and triparanol both markedly enhance the sensitivity of drug-resistant cells to doxorubicin and vinblastine but do not have an effect on anthracycline-sensitive cells. This enhanced sensitivity is associated with increased drug accumulation. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not implicate this mechanism in the enhancement of cell sensitivity to doxorubicin. We suggest that this effect might be related to alterations of the cell membrane lipid domain induced by perhexiline maleate and triparanol, which result in decreased structural order of plasma membrane lipids and permit increased drug accumulation.

Topics: Animals; Calcium Channel Blockers; Cell Line; Doxorubicin; Drug Resistance; Leukemia P388; Leukemia, Experimental; Membrane Lipids; Mice; Perhexiline; Vinblastine

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.

Topics: Animals; Biological Transport; Cell Division; Cell Survival; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Kinetics; Leukemia P388; Leukemia, Experimental; Mice; Mice, Inbred Strains; Perhexiline; Vinblastine