Reversion of P-Glycoprotein-Mediated Multidrug Resistance in Human Leukemic Cell Line by Carnosic Acid

Xiao-Ning Yu ； Xue-Liang Chen ； Hao Li ； Xiang-Xin Li ； Hui-Qing Li ； Wen-Rui Jin

《The Chinese Journal of Physiology》 51卷6期 (2008/12) Pp. 348-356

並列摘要

One of the common hindrances to successful chemotherapy is the development of multidrug resistance (MDR) by tumor cells to multiple chemotherapeutic agents. In this regard, P-glycoprotein (P-gp) acts as an energized drug pump that reduces the intracellular concentration of drugs, even of structurally unrelated ones. The modulators of P-gp function can restore the sensitivity of MDR cells to anticancer drugs. Therefore, to develop effective drug-resistance-reversing agents, we evaluated the P-gp modulating potential of carnosic acid (CA) in multidrug-resistant K562/AO2 cells in the present study. The reversing effect of CA was evaluated by determining the inhibition rates of cell viability with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT) assays. The intracellular adriamycin fluorescence intensity and the expression of P-gp were measured by flow cytometry (FCM). Meanwhile, the subcellular distribution of adriamycin was detected via Laser Scanning Confocal Microscopy (LSCM). The mRNA expression of mdr1was then detected via semiquantitative reverse transcription polymerase chain reaction (RT-PCR). The findings showed that CA decreased apparently the Inhibition Concentration 50% (IC50) of adriamycin by increasing its intracellular concentration and thus enhancing the sensitivity of K562/AO2 cells. Adriamycin was distributed evenly in the cytoplasm when the cells were treated with CA. The expression of mdr1 was decreased. Overall, the results indicated that CA can serve as a novel, non-toxic modulator of MDR, and it can reverse the MDR of K562/AO2 cells in vitro by increasing intracellular adriamycin concentration, down-regulating the expression of mdr1, and inhibiting the function of P-gp.

並列關鍵字

carnosic acid ； multidrug resistance ； P-glycoprotein ； reverse

參考文獻

Barrand, M.A.,Rhodes, T.,Center M.S.,Twentyman, P.R.(1993).Chemosensitisation and drug accumulation effects of cyclosporine A, PSC 833 and verapamil in human MDR large cell lung cancer cells expressing a 190k membrane protein distinct from Pglycoprotein.Eur. J. Cancer.29,408-415.

Baylor, S.M.,Hollingworth, S.(2000).Measurement and interpretation of cytoplasmic [Ca2+] signals from calcium-indicator dyes.News Physiol. Sci..15,19-26.

Chen, L.,Xu, X.P.,Wang, J.M.,Fei, X.H.,Gao, L.,Zhou, H.,Huang, Z.X.(2003).Reversal of multidrug resistance in leukemia cell line by cyclosporin a combining with tamoxifen and interferon-α.J. Leukemia Lymphoma.12,135-138.

Danilenko, M.,Wang, Q.,Wang, X.,Levy, J.,Sharoni, Y.,Studzinski, G.P.(2003).Carnosic acid potentiates the antioxidant and prodifferentiation effects of 1α,25-dihydroxyvitamin D3 in leukemia cells but does not promote elevation of basal levels of intracellular calcium.Cancer Res..63,1325-1332.

Danilenko, M.,Wang, X.,Studzinski G.P.(2001).Carnosic acid and promotion of monocytic differentiation of HL60-G cells initiated by other agents.J. Natl. Cancer Inst..93,1224-1233.