Carcinogenesis Advance Access originally published online on January 16, 2004
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Carcinogenesis, Vol. 25, No. 6, 941-949,
June 2004
Carcinogenesis vol.25 no.6 © Oxford University Press 2004; all rights reserved.
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Reversal of P-glycoprotein-mediated multidrug resistance by diallyl sulfide in K562 leukemic cells and in mouse liver
Environmental Carcinogenesis Division, Industrial Toxicology Research Centre, PO Box 80, M.G.Marg, Lucknow-226001, India
1 To whom correspondence should be addressed. Fax: +91 522 2228227; Email: yogeshwer_shukla{at}hotmail.com
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 x 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.
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