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 anticancer-drug cytotoxicity in wild-type and multidrug-resistant (MDR) mammalian cells. We show here that the chemosensitizers, reserpine and verapamil, display a dramatic potentiation of taxol, anthracycline and Vinca alkaloids cytotoxicity in P-glycoprotein-(P-gp)-deficient hamster and human nasopharyngeal carcinoma cells. We have therefore utilized this phenomenon to probe for the putative P-gp-independent component of cytotoxicity chemosensitization. These chemosensitizers yielded a marked increase in the accumulation of taxol in parental hamster and human carcinoma cells that are devoid of P-gp. These chemosensitizers and non-ionic detergents brought about a pronounced increase in the accumulation of structurally and mechanistically diverse lipophilic chromophores in parental and MDR hamster cells. Furthermore, non-toxic concentrations of these non-ionic detergents yielded a marked potentiation of taxol cytotoxicity in parental cells. These findings were consistent with a chemosensitizer-mediated, P-gp-independent increase in membrane permeability. Thus, several aspects of chemosensitizers' interaction with lipid bilayers and biomembranes were studied. In this respect, like various mild detergents, chemosensitizers induced a dose-dependent leakage of carboxyfluorescein encapsulated in liposomes. Like specialized membrane fluidizers, various chemosensitizers induced a dose-dependent membrane fluidization (and sometimes rigidification) in both liposomes and various wild-type and MDR animal and human cells, as revealed by diphenylhexatriene fluorescence polarization. Furthermore, a favorable correlation was observed between the ability of chemosensitizers to permeabilize lipid bilayers and their capacity to potentiate anticancer-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 achieving potentiation of anticancer-drug cytotoxicity in wild-type and MDR mammalian cells. This study offers a basis for the chemosensitizer-mediated potentiation of drug toxicity to healthy tissues, thus emphasizing the importance of a prior evaluation of the potential untoward toxicity when simultaneously using MDR chemosensitizers and cytotoxic agents in the clinic.
Drori
S
S
Department of Biology, Technion-Israel Institute of Technology, Haifa.
Eytan
G D
GD
Assaraf
Y G
YG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D006224:Cricetinae; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012110:Reserpine; D014700:Verapamil