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

Maurizio Viale, Cinzia Cordazzo, Daniela De Totero, Roberta Budriesi, Camillo Rosano, Alberto Leoni, Pierfranco Ioan, Cinzia Aiello, Michela Croce, Aldo Andreani, Mirella Rambaldi, Patrizia Russo, Alberto Chiarini, Domenico Spinelli

Research output: Contribution to journalArticlepeer-review

Abstract

Summary: 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% IC50 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.

Original languageEnglish
Pages (from-to)98-109
Number of pages12
JournalInvestigational New Drugs
Volume29
Issue number1
DOIs
Publication statusPublished - Feb 2011

Keywords

  • 1,4-dihydropyridines
  • Antitumor agents
  • Apoptosis
  • Multidrug resistance
  • Pgp-170

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Fingerprint Dive into the research topics of 'Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: An in vitro analysis'. Together they form a unique fingerprint.

Cite this