Role of Scaffold Proteins in Functional Alteration of Small Intestinal P-glycoprotein by Anti-cancer Drugs

Since there is accumulating evidence to indicate that introduction of early palliative care for cancer patients may improved their quality of life or survival rates, the number of patients receiving pain relief by narcotic analgesics in conjunction with chemotherapy is predicted to increase. Therefore to provide effective combination treatments it is important to evaluate basic evidence regarding drug-drug interactions between anti-cancer drugs and narcotics. We have focused on P-glycoprotein (P-gp), a drug efflux transporter, in small intestine where the absorption process of drugs administered via oral route is greatly limited. Then, we revealed that repeated oral treatment with etoposide (ETP) increases P-gp levels in the small intestinal membrane via RhoA/ROCK activation, leading to decrease in analgesia of morphine, a P-gp substrate drug, with alteration of its disposition after oral administration. Furthermore, we found that activation of ezrin/radixin/moesin (ERM), scaffold proteins that regulate plasma membrane localization or function of certain plasma membrane proteins such as P-gp, are involved in this mechanism. Of particular interest is that among ERM proteins, radixin may contribute, at least in part, to increased expression of P-gp in the small intestine under repeated oral treatment with ETP.