A novel non-natural nucleoside that influences P-glycoprotein activity and mediates drug resistance.
Multidrug resistance during cancer chemotherapy is commonly acquired by overexpression of the ATP binding cassette transporter, P-glycoprotein (P-gp). As such, inhibitors that target P-gp activity represent potential therapeutic agents against this form of drug resistance. This study evaluated the ability of various non-natural nucleosides that mimic the core structure of adenosine to modulate drug resistance by inhibiting the ATPase activity to P-gp. Of several analogues tested, only one novel non-natural nucleoside, 5-cyclohexylindolyl-2'-deoxyribose (5-CHInd), behaves as a P-gp inhibitor. Although 5-CHInd is an adenosine analogue that should block the binding of ATP, the non-natural nucleoside surprisingly stimulates the ATPase activity of P-gp in vitro. However, 5-CHInd is not an exportable substrate for P-gp as it is not transported across an MDCK-MDR1 monolayer. In addition, 5-CHInd differentially modulates MDR by decreasing or increasing the cytotoxicity of several chemotherapeutic agents. Although 5-CHInd displays variable activity in modulating the efflux of various drugs by P-gp, there is a correlation between changes observed in the drug-stimulated ATPase catalytic efficiency induced by 5-CHInd and its effect on drug efflux. The paradoxical behavior of 5-CHInd is rationalized within the context of contemporary models of P-gp function. In addition, the data are used to develop a predictive in vitro model for rapidly identifying potential drug-drug interactions with P-gp.
Eng
Kevin T
KT
Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Berdis
Anthony J
AJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003855:Deoxyribose / Q000737:chemistry*; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D015394:Molecular Structure; D009705:Nucleosides / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009705:Nucleosides; D003855:Deoxyribose; D000251:Adenosine Triphosphatases