Reversal of Multidrug Resistance in Friend Leukemia Cells by Dexniguldipine-HCl

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 1993 Jan 1

PMID 8462120

Citations 3

Authors

A Reymann

G Looft

C Woermann

M Dietel

R Erttmann

Affiliations

Soon will be listed here.

Abstract

Dexniguldipine-HCl (DNIG)--a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MDR)--was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR), or mitoxantrone (MITO) in resistant F4-6RADR cells to the very levels observed in drug-sensitive F4-6 precursor cells. In parallel with the increase in DNR content (F4-6RADR, solvent: 303 +/- 27 pmol/mg protein; DNIG (3.3 mumol/l): 1,067 +/- 174 pmol/mg protein; F4-6P, solvent: 948 +/- 110 pmol/mg protein; n = 8-9, SEM), the amount of DNR tightly bound to the acid precipitate pellet obtained from F4-6RADR (i.e., protein, DNA, RNA) increased 3.9-times to the levels observed in sensitive F4-6 cells. The main pyridine metabolite of DNIG displayed similar activity. Concentration-response analysis revealed that DNIG and R,S-verapamil (VER) induced 100% reversal of the DNR accumulation shortage associated with the MDR phenotype but DNIG was 8 times more potent than VER (50% inhibitory concentration (IC50), 0.73 vs 5.4 mumol/l). In keeping with the accumulation assay, DNIG was about 10 times more potent than VER in sensitizing F4-6RADR cells to the cytostatic and cytotoxic effects of DNR in proliferation assays. In conclusion, DNIG is a potent in vitro modulator, improving (a) the accumulation of anthracycline-like cytostatics, (b) drug access to cellular binding sites, and (c) the cytostatic action of DNR in F4-6RADR leukemia cells of the MDR phenotype.

Citing Articles

Dexniguldipine hydrochloride, a protein-kinase-C-specific inhibitor, affects the cell cycle, differentiation, P-glycoprotein levels, and nuclear protein phosphorylation in Friend erythroleukemia cells.

Patterson K, Beckman B, Klotz D, Mallia C, Jeter Jr J J Cancer Res Clin Oncol. 1996; 122(8):465-75.

PMID: 8698746 DOI: 10.1007/BF01187158.

Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model.

van de Vrie W, Schellens J, Loss W, Kolker H, Verwey J, Stoter G J Cancer Res Clin Oncol. 1996; 122(7):403-8.

PMID: 8690750 DOI: 10.1007/BF01212879.

Secondary combined resistance to the multidrug-resistance-reversing activity of cyclosporin A in the cell line F4-6RADR-CsA.

Dietel M, Herzig I, Reymann A, Brandt I, Schaefer B, Bunge A J Cancer Res Clin Oncol. 1994; 120(5):263-71.

PMID: 7907333 DOI: 10.1007/BF01236382.

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