Effect of alpha-interferon on P-glycoprotein expression and function and on verapamil modulation of doxorubicin resistance.

Cancer Research

PubMedID: 7910518

Kang Y, Perry RR. Effect of alpha-interferon on P-glycoprotein expression and function and on verapamil modulation of doxorubicin resistance. Cancer Res. 1994;54(11):2952-8.
Human alpha-interferon (IFN-alpha) is one of the three major classes of interferons which possess antiviral, antiproliferative, and immunomodulatory activities. We recently reported synergism between IFN-alpha and tamoxifen in the modulation of doxorubicin (DOX) cytotoxicity and accumulation in multidrug resistant Chinese hamster ovary ChR C5 cells (Y. Kang and R. R. Perry, Cancer Res., 53: 3040-3045, 1993), but the mechanism was uncertain. In the present study, IFN-alpha (500 units/ml) pretreatment of ChR C5 cells similarly increased verapamil (VPL) modulation of DOX cytotoxicity in a time-dependent manner. Measurement of intracellular DOX fluorescence showed a parallel increase in DOX accumulation. Western blot analysis revealed that IFN-alpha induced a time-dependent increase in p-glycoprotein (p-gp) expression, accompanied by an increase of mdr-1 mRNA as measured using Northern analysis. MDR-1 gene copy number measured using Southern analysis remained unchanged. Assay of specific photoaffinity labeling of p-gp by [3H]-azidopine showed that, although IFN-alpha is not a substrate of p-gp, it significantly increased the ability of VPL to bind to p-gp. These data suggest that IFN-alpha may effect the expression of p-gp in multidrug-resistant ChR C5 cells by transcriptional or posttranscriptional control of mdr-1 gene expression. IFN-alpha enhances the ability of VPL to modulate DOX cytotoxicity and accumulation, possibly by altering the accessibility of p-gp binding site(s) to VPL. By using relatively low concentrations of IFN-alpha and VPL it may be possible to develop less toxic regimens to reverse multidrug resistance.