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Overcoming Multidrug Resistance in Vitro and in Vivo by a Novel P-glycoprotein Inhibitor 1416.

Biosci Rep. 2012 Jul 3;

Authors: Xu Y, Zhi F, Xu G, Tang X, Lu S, Wu J, Hu Y


Multidrug resistance (MDR) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by over-expression of P-glycoprotein (P-gp). Much effort has been devoted to develop P-gp inhibitors to modulate MDR. However, none of the inhibitors have been successful on the market. 1- (2, 6-dimethylphenoxy)-2-(3, 4-dimethoxyphenylethylamino) propane hydrochloride (phenoprolamine hydrochloride, 1416) is a new verapamil analogue with a higher IC50 for blocking calcium channel currents than verapamil. Here we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of vinblastine in P-gp overexpressed human multidrug-resistant K562/ADM and KBV cells´╝îbut had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rhodanmine123 content in MDR cells. Human K562/ADM xenograft- nude mice model verified that 1416 potentiate the antitumor activity of vinblastine in vivo. RT-PCR and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggested that 1416 would be a promising agent for overcoming MDR in cancer chemotherapy.

PMID: 22757751 [PubMed - as supplied by publisher]