Carcinogenesis Advance Access published online on January 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh060
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Environmental Carcinogenesis Division, Industrial Toxicology Research Centre, P.O. Box 80, M.G. Marg, Lucknow-226001, India
* Corresponding author. E-mail: yogeshwer_shukla{at}hotmail.com.
Received 6 August 2003
; revised 11 December 2003
; accepted 12 December 2003
Multidrug resistance (MDR) mediated by the over-expression 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 MDR 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) towards the cytotoxicity of vinblastine (VBL) by progressive adaptation of the parental sensitive K562 cells to VBL. Crossresistance of K562/R was found between vincristine (VCR), doxorubicin (DXR) and other antineoplastic agents. A non-toxic concentration of DAS (8.75 x 10-3M) 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 showed 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 the vinca alkaloid induced P-gp overexpression in mouse hepatocytes. Quantitation of immunostained tissue sections with image analysis showed that reduction in P-gp levels was up to the extent of 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.
Reversal of P-glycoprotein mediated multidrug resistance by diallyl sulfide in K562 leukemic cells and in mouse liver
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