Cytotoxic and multidrug resistance reversal activities of novel 1,4-dihydropyridines against human cancer cells

Multidrug resistance (MDR) caused by P-glycoprotein (P-gp, ABCB1, MDR 1) transporter over expression in cancer cells substantially limits the effectiveness of chemotherapy. 1,4-Dihydropyridines (DHPs) derivatives possess several pharmacological activities. In this study, 18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moieties at C-3 and C-5 positions, respectively, as well as nitrophenyl or hetero aromatic rings at C-4 were synthesized and tested for MDR reversal with the aim of establishing a structure activity relationship (SAR) for these agents. Effect of these compounds on P-gp mediated MDR was assessed in P-gp over expressing MES-SA/DX5 doxorubicin resistant cells by flow cytometric detection of rhodamine 123 efflux. MDR reversal was further examined as the alteration of doxorubicin's IC50 in MES-SA/DX5 cells in the presence of DHPs by MIT assay and was compared to nonresistant MES-SA cells. Direct anticancer effect was examined against 4 human cancer cells including HL-60, K562, MCF-7 and LS180. Calcium channel blocking (CCB) activity was also measured as a potential side effect. Most DHPs, particularly compounds bearing 3-nitrophenyl (A2B2 and A3B2) and 4-nitrophenyl (A3B1 and A4B1) moieties at C-4 significantly inhibited rhodamine 123 efflux at 5-25 mu M, showing that the mechanism of MDR reversal by these agents is P-gp transporter modulation. Same derivatives were also able to selectively lower the resistance of MES-SA/DX5 to doxorubicin. A2B2 bearing ethyl carboxylate at C-5 had also high direct antitumoral effect (IC50 range: 3.77-15.60 mu M). Our findings suggest that SAR studies of DHPs may lead to the discovery of novel MDR reversal agents. (C) 2014 Elsevier B.V. All rights reserved.