POTENTIATION OF ANTICANCER-DRUG CYTOTOXICITY BY MULTIDRUG-RESISTANCE CHEMOSENSITIZERS INVOLVES ALTERATIONS IN MEMBRANE FLUIDITY LEADING TO INCREASED MEMBRANE-PERMEABILITY

We are studying the mechanism underlying chemosensitization of antican cer-drug cytotoxicity in wild-type and multidrug-resistant (MDR) mamma lian cells. We show here that the chemosensitizers, reserpine and vera pamil, display a dramatic potentiation of taxol, anthracycline and Vin ca alkaloids cytotoxicity in P-glycoprotein-(P-gp)-deficient hamster a nd human nasopharyngeal carcinoma cells. We have therefore utilized th is phenomenon to probe for the putative P-gp-independent component of cytotoxicity chemosensitization. These chemosensitizers yielded a mark ed increase in the accumulation of taxol in parental hamster and human carcinoma cells that are devoid of P-gp. These chemosensitizers and n onionic detergents brought about a pronounced increase in the accumula tion of structurally and mechanistically diverse lipophilic chromophor es in parental and MDR hamster cells, Furthermore, non-toxic concentra tions of these non-ionic detergents yielded a marked potentiation of t axol cytotoxicity in parental. cells. These findings were consistent w ith a chemosensitizer-mediated, P-gp-independent increase in membrane permeability. Thus, several aspects of chemosensitizers' interaction w ith lipid bilayers and biomembranes were studied. In this respect, lik e various mild detergents, chemosensitizers induced a dose-dependent l eakage of carboxyfluorescein encapsulated in liposomes. Like specializ ed membrane fluidizers, various chemosensitizers induced a dose-depend ent membrane fluidization (and sometimes rigidification) in both lipos omes and various wild-type and MDR animal and human cells, as revealed by diphenylhexatriene fluorescence polarization. Furthermore, a favor able correlation was observed between the ability of chemosensitizers to permeabilize lipid bilayers and their capacity to potentiate antica ncer-drug cytotoxicity. Thus, we propose that chemosensitizer-mediated changes in the physical properties of biomembranes, including altered fluidity and increased permeability, may be important factors in achi eving potentiation of anticancer-drug cytotoxicity in wild-type and MD R mammalian cells. This study offers a basis for the chemosensitizer-m ediated potentiation of drug toxicity to healthy tissues, thus emphasi zing the importance of a prior evaluation of the potential untoward to xicity when simultaneously using MDR chemosensitizers and cytotoxic ag ents in the clinic.