Multidrug Resistant Gene MDR1 Contributes to Development of Imatinib-Resistance in Ph(+) Acute Lymphoblastic Leukemia Cell Line SUP-B15RI

LIN Juan, XING Hong-yun, GONG Yu-ping, YANG Xi, GUO Yong, SHAN Qing-qing, ZHOU Rui-qing

Abstract

To investigate the contribution of multidrug-resistant gene MDR1 to development of imatinib-resistance in Ph(+)acute lymphoblastic leukemia cell line SUP-B15/RI. Methods RT-PCR was used to examine MDR1 mRNA levels, cytotoxic effects of imatinib (IM), daunorubicin (DNR), vincristine (VCR), etoposide (VP-16) and the synergetic antiproliferation with P-gp inhibitor verapamil on sensitive SUP-B15 and SUP-B15/RI cell lines were detected by the MTT assay. The P-gp function was measured by flow cytometry. Results Increased expression of MDR1 gene in SUP-B15/RI than that of SUP-B15 cell line (P<0.05) was observed when detected with RT-PCR. The IC50 values of SUP-B15/RI cell line inhibited by IM, DNR, VCR, VP-16 for 72 hours was higher than that of SUP-B15 (P<0.05) and the resistant factor (RF) was (20.52±2.34),(10.33±1.88),(9.78±1.27),(3.84±0.69) respectively. The IC50 values of IM, DNR, VCR, VP-16 combined with P-gp inhibitor verapamil were decreased in SUP-B15/RI cells (P<0.05), reversal of drug resistance was (1.44±0.43),(3.20±0.17),(1.44±0.12),(1.33±0.14) respectively. The activity of P-gp in SUP-B15/RI measured by flow cytometry was higher than that of P-gp in SUP-B15/RI cell line. Conclusion The overexpression of MDR1 mRNA and higher activity of P-gp is partially responsible for acquiring of imatinib resistance in SUP-B15/RI cell line. P-gp inhibitor verapamail can partially restored the sensitivity of the SUP-B15/RI cell line to anticancer agents.

 

Keywords: Imatinib resistance, MDR1/P-gp, SUP-B15 cell line, Ph(+)acute lymphoblastic leukemia


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References


Thomas DA. Stefa Faderl S. Corte J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004; 103 (12);4396-4407.

Thomas DA. Philadelphia chromosome-positive acute lymphocytic leukemia;a new era ofchallenges. Hematology Am So Hematol Educ Program,2007:435-443.

Nimmanapalli R. Bhalla K. Mechanisms of resistance to imatinib mesylate in Bcr-Abl-positive leukemias. Curr Opin Oncob 2002; 14 (6): 616-620.

Mauro MJ. Defining and managing imatinib resistance. Hematology Am Soc Hematol Educ Program.2006:219-225.

Radujkovic A.Schad M.Topaly J,et al. Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL—inhibition of P-glycoprotein by 17- AAG. Leukemia, 2005; 19(7): 1198-1206.

Hirayama C, Watanabe H, Nakashima R. et al. Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1 «contributes to acquisition of imatinib-resistance in K562 cells. Pharm Res, 2008;25(4);827-835.

Sharom FJ. ABC multidrug transporters; structure, function and role in chemoresistance. Pharmacogenomics, 2008; 9( 1 ): 105-127.

Oostendorp RL,Buckle T.Beijnen JHw al. The effect of P-gp (Mdrla/lb), BCRP (Bcrpl) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Invest New Drugs,2009;27(1) :31-40.

Hamada A.Wantanabe H, Nakashima H, el at. Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther,2003;307(2);824-828.


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