REVERSAL OF ANTICANCER MULTIDRUG-RESISTANCE BY THE ARDEEMINS

Two ''reverse prenyl'' hexahydropyrroloindole alkaloids, 5-N-acetylard eemin and 5-N-acetyl-8-demethylardeemin, were evaluated as reversal ag ents in cells exhibiting a multidrug resistant (MDR) phenotype. These ardeemins (i) reversed drug resistance to vinblastine (VBL) or to taxo l as much as 700-fold at relatively noncytotoxic concentrations in vit ro; (ii) as a single agent at high concentrations killed MDR cells mor e efficaciously than the respective parent wild-type cells; and (iii) exhibited strong synergistic effects with doxorubicin (DX) and VBL aga inst the growth of MDR neoplastic cells, and to a lesser extent, of th e parent wild-type cells. Mechanistic studies showed that photoaffinit y labeling of P-glycoprotein (Pgp) with [H-3] azidopine was competitiv ely inhibited by the ardeemins. Resistance to DX in MDR-[Pgp(+) and MD -associated protein (MRP)(+)], MDR-Pgp(+), lung resistance protein (LR P)(+)-expressing, and wild-type lung cancer cells were reversed 110- t o 200-fold, 50- to 66-fold, 7- to 15-fold, and 0.9- to 3-fold, respect ively, by 20 mu M of the ardeemins. Moreover, these compounds increase d the intracellular accumulation of VBL and markedly decreased its eff lux. Finally, in vivo combination studies demonstrated that nontoxic d oses of the ardeemins with DX significantly improved the chemotherapeu tic effects in B6D2F(1) mice bearing DX-resistant P388 leukemia, and n ude mice bearing human MX-I mammary carcinoma xenografts. The above fe atures indicate that the ardeemins may have utility in the therapy of cancer.