Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

Abstract

We report herein the reversal of multidrug resistance-1 (MDR1) in A2780/DX3 cells by the two nifedipine-like compounds 1 and 2 that are part of a library of 1,4-dihydropyridines (1,4-DHPs) calcium-channel modulators bearing in C-4 a different substituted imidazo[2,1-b]thiazole system. By methylthiazol tetrazolium (MTT) assay, cytofluorimetry, and fluorescence microscopy we evaluated their ability to reverse MDR in our cell system. Moreover, together with compound 3 (the diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one) we analyzed their ability to potentiate the triggering of apoptosis after exposure to doxorubicin, through the nuclear morphological analysis after 4',6-diamidino-2-phenylindole (DAPI), the fluorescein isothiocyanate (FITC)-Annexin-V/propidium iodide (PI) staining and the caspase activity determination. Our results demonstrate that compounds 1 and 2, at concentrations showing a very low (5%) or absent inhibition of cell proliferation, in combination with doxorubicin enhance its antiproliferative activity (from 30% to 54% IC(50) reduction) in A2780/DX3 cells through an increase of doxorubicin intracellular accumulation. These compounds together with compound 3, which has already been demonstrated to act as a potent inhibitor of MDR1 function, were also able to significantly potentiate the activation of the apoptosis machinery triggered by the exposure to doxorubicin. In conclusion, our results identify two new molecules structurally related to the calcium-channel blocker nifedipine, but characterized by a very low LTCC blockers activity, able to potentiate the antiproliferative and apoptotic activities of doxorubicin through an increase of its intracellular concentration likely caused by the inhibition of MDR1 function.

Disappearance of a metastatic brain tumor and achievement of long-term survival with a good quality of life after a combination of systemic chemotherapy with the P-glycoprotein inhibitor nifedipine in a patient with ovarian cancer

“…One of them is nifedipine, which blocks type L calcium channels [4][5][6][7]9]. In vitro, nifedipine-like compounds inhibit the multidrug resistance-1 gene function in doxorubicin-resistant ovarian cancer cells and enhance the doxorubicin-mediated inhibition of tumor cell proliferation; thus, such compounds may trigger apoptosis [9]. In a rat glioma model, nifedipine was found to selectively enhance drug delivery to malignant brain tumors without affecting normal brain tissue [5].…”

Process optimization and eco-friendly/greener synthesis of some n-aryl/heteryl acetoacetamides

“…In particular, they play key role as intermediates in the synthesis of pyridines and pyrimidines (Dyachenko, 2005;Habashi et al, 1986;Lebed et al, 2012;Kumar et al, 2009;Riad et al, 1989;Sadek et al, 2011;Viale et al, 2011;Yadav et al, 2003;Yadav et al, 2011). They are prepared by the two component reaction of alkyl acetoacetate and different aromatic /hetero aromatic amines (Desai et al, 2001).…”

Differential effects of calcium antagonists on ABCG2/BCRP-mediated drug resistance and transport in SN-38-resistant HeLa cells

“…Therefore, the effects of various agents on each transporter must be examined individually. In 1981, the inhibitory effect of verapamil on ABCB1/MDR1 function was reported (6), and then, the effects of calcium antagonists on ABCB1/MDR1 were extensively investigated (7)(8)(9)(10). We also examined the effects of calcium antagonists on ABCB1/MDR1-mediated transport and resistance, which varied according to the type of calcium antagonist used (11).…”