Studies of in vivo efficacy of flavonoid dimers in modulating p-glycoprotein (P-GP) mediated drug resistance

Abstract

A series of apigenin based novel flavonoid dimers were synthesized to tackle cancer MDR mediated by P-gp. Lead optimization through the introduction of an amine group within the PEG linker of parent compound 61 has led to the discovery of FD18. FD18 is more potent than 61, with an EC50 towards PTX decreased from 360 nM to 148nM and enhanced aqueous solubility. FD18, together with its derivatives, were characterized in vivo withthe use of a newly established LCC6/MDR P-gp overexpressed human cancer nude mice model. This model is highly resistant to PTX treatment at 12 mg/kg (q.o.d. x 4 for 2 cycle), making it favorable to become an ideal testing platform. Subsequent treatment of these flavonoid compounds at 45 mg/kg together with PTX at 12 mg/kg (q.o.d. x 12) had demonstrated tumor inhibition effects, in which, FD18 was the most potent compound resultedin apromising %T-C of 54%. The safety profile of FD18 was also demonstrated through injections to healthy Balb/c mice and histopathological studies. No treated mice exerted toxicity deaths or weight loss >15% as well as cellular toxicities. DMPK study of FD18 has proposed one of its metabolite is an active P-gp inhibitor. This metabolite, namely FM04, has significantly increased in its aqueous solubility with a clogP value of 4.06 (clogP for FD18 is 7.07) and 50% more potent compared to FD18 in reversing PTX resistance from LCC6/MDR cells (EC50 = 70nM). It was compared with FD18 with essentially the same in inhibiting DOX transport and the role as a P-gp substrate. Finally, FM04 was better in in vivo P-gp modulating activity towards PTX treatment over FD18 with a %T-C of 57%. Together with its druggability as defined by the Lipinski Rule of 5, makes FM04 more favorable than FD18 as adrug candidate.