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Overexpression of P-glycoprotein in heat-and/or drug-resistant hepatoma variants

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Abstract

We have earlier isolated a glucocorticoid-resistant, dedifferentiated rat hepatoma variant, the clone 2, which exhibited deficient stress activation of the major stress-inducible heat-shock protein hsp68.Multidrug-resistant variants were isolated from clone 2 cells using increasing concentrations of colchicine. The induction deficiency of hsp68 was maintained in the colchicine-resistant clone 2 cells grown for several months in the presence of 1 μg/ml colchicine (termed ashighly multidrug-resistant variant) indicating that this heat-shock protein is not involved in the multidrug resistance. No alteration of the protein synthesis pattern was observed except the strong increase of the P-glycoprotein, which correlated with high level of corresponding mRNA. Stableheat-resistant variants of clone 2 were also isolated, which showed increaseddrug resistance to several drugs, i.e. they becamemoderately multidrug-resistant. This moderate multidrug resistance of the heat-resistant variants was further increased by stepwise selection with colchicine (highly multidrug-resistant heat-resistant variants). The levels of P-glycoprotein mRNA and protein were elevated both in the heat-resistant, non drug selected, moderately drug-resistant and in heatresistant, colchicine selected, highly drug-resistant variants. Decreased retention of antitumor drugs was observed in all multidrug-resistant variants indicating that P-glycoprotein was functional. Verapamil increased doxorubicin retention and cytotoxicity significantly. Our results showing that severely stressed hepatoma cells overexpressed the multidrug resistance gene(s) raise the possibility that the P-glycoprotein may participate in protection against enviromental stress such as heat.

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Abbreviations

hsp:

heat-shock protein

MDR:

multidrug resistance

P-gp:

P-glycoprotein

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Authors and Affiliations

  1. Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, POB 521, H-6701, Szeged, Hungary

    Melinda Pirity, Anna Hevér-Szabó & Anikó Venetianer

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  1. Melinda Pirity
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  2. Anna Hevér-Szabó
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  3. Anikó Venetianer
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Pirity, M., Hevér-Szabó, A. & Venetianer, A. Overexpression of P-glycoprotein in heat-and/or drug-resistant hepatoma variants. Cytotechnology 19, 207–214 (1996). https://doi.org/10.1007/BF00744214

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