Journal Article

Reversal of P-glycoprotein-mediated multidrug resistance by diallyl sulfide in K562 leukemic cells and in mouse liver

Annu Arora, Kavita Seth and Yogeshwer Shukla

in Carcinogenesis

Volume 25, issue 6, pages 941-949
Published in print June 2004 | ISSN: 0143-3334
Published online June 2004 | e-ISSN: 1460-2180 | DOI:
Reversal of P-glycoprotein-mediated multidrug resistance by diallyl sulfide in K562 leukemic cells and in mouse liver

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Multidrug resistance (MDR) mediated by the overexpression of drug efflux protein P-glycoprotein (P-gp) is one of the major obstacles to successful cancer chemotherapy. P-gp acts as an energy-dependent drug efflux pump, reducing the intracellular concentration of structurally unrelated drugs. Modulators of P-gp function can restore the sensitivity of multidrug-resistant cells to such drugs. In the present study, we evaluated the P-gp modulatory potential of diallyl sulfide (DAS), a volatile organosulfur compound present in garlic, known to possess many medicinal properties, including antimutagenic and anticarcinogenic activities. For in vitro studies, K562 leukemic cells were made resistant (K562/R) to the cytotoxicity of vinblastine (VBL) by progressive adaptation of the sensitive K562 parental cells to VBL. Cross-resistance of K562/R was found between vincristine (VCR), doxorubicin and other antineoplastic agents. A non-toxic concentration of DAS (8.75 × 10−3 M) enhanced the cytotoxic effects of VBL and another vinca alkaloid, VCR, time dependently in VBL-resistant human leukemia (K562/R10) cells but had no effect on the parent (K562/S) cells. The results show that DAS decreased the induced levels of P-gp in resistant cells back to the normal levels as analyzed both qualitatively and quantitatively by western blotting and immunocytochemistry. Furthermore, in vivo combination studies showed that DAS effectively inhibited vinca alkaloid-induced P-gp overexpression in mouse hepatocytes. Quantitation of immunostained tissue sections with image analysis showed that the reduction in P-gp levels was up to 73% for VBL- and 65% for VCR-induced drug resistance. The above features thus indicate that DAS can serve as a novel, non-toxic modulator of MDR and can be used as a dietary adjuvant.

Keywords: DAS, diallyl sulfide; DMBA, 7,12-dimethyl benzanthracene; DMSO, dimethyl sulfoxide; DXR, doxorubicin; MDR, multidrug resistance; MTT, 3-(4,5-dimethylthiazole-2-yl)2-diphenyl tetrazolium bromide; P-gp, P-glycoprotein; PBS, phosphate-buffered saline; VPL, verapamil; VBL, vinblastine; VCR, vincristine

Journal Article.  5629 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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