L-1416,a novel MDR reversing agent with possible reduced calcium antagonism

Background: multidrug efflux transporter p-glycoprotein (p-gp) is highly expressed on membrane of tumor cells and supposed to be implicated in the resistance to tumor chemotherapy. however,currently none of p-gp inhibitors has been approved by food and drug administration not only due to toxicity but also lack of efficacy in clinical trials.methods: to solve the problem,our lab synthesized a novel compound named 1416 [1-(2,6-dimethylphenoxy)-3,4-dimethoxyphenylethylamino) propane hydrochloride] with the hope of high p-gp inhibition and low side effects. caco-2 cell monolayer and tumor bearing mice were used to evaluate the p-gp inhibition of 1416 in vitro and in vivo,respectively. one of its potential side effects,calcium antagonism was also evaluated.results: results showed that 1416 showed a similar p-gp inhibition as verapamil in caco-2 cell monolayer. no significant difference was observed in antitumor enhancement when the optical isomers of 1416 (d-1416 and l-1416) were co-administered with vinblastine. in calcium antagonism,l-1416 showed less calcium inhibition than both d-1416 and verapamil.conclusion: the novel compound 1416 could significantly increase the antitumor effects of cytotoxic drugs and one of its optical isomers,l-1416,might be more promising due to its potential low calcium antagonism. © 2014 institute of pharmacology,polish academy of sciences. published by elsevier urban & partner sp. z o.o. all rights reserved.