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. and Berdis, Anthony J., "A Novel Non-Natural Nucleoside That Influences P-Glycoprotein Activity and Mediates Drug Resistance" (2010). Chemistry Faculty Publications. 228.