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  • Title: Proteasome inhibitor bortezomib overcomes P-gp-mediated multidrug resistance in resistant leukemic cell lines.
    Author: Zheng B, Zhou R, Gong Y, Yang X, Shan Q.
    Journal: Int J Lab Hematol; 2012 Jun; 34(3):237-47. PubMed ID: 22145750.
    Abstract:
    INTRODUCTION: To study the effect of bortezomib alone or in combination with daunorubicin (DNR) on an mdr1 single-factor drug-resistant leukemia cell line K562/MDR1, a multifactor-resistant cell line K562/A02, a drug-sensitive cell line K562, and primary cells from acute myeloid leukemia patients. METHODS: The cell lines were exposed to bortezomib, DNR, and bortezomib plus DNR, and cell proliferation, cell cycle, apoptosis rate, and expression of MDR1/BCL2 were analyzed. RESULTS: Bortezomib potently inhibited growth and increased the apoptosis rate in the cell lines. In K562/MDR1 and K562/A02, the calcium channel blocker verapamil reduced the 50% inhibitory concentration and apoptosis rate of DNR, a P-gp protein substrate, but not of bortezomib. Bortezomib plus DNR had synergistic effect on antiproliferation (synergistic ratio > 1). Apoptosis was substantially more increased by the combination of two drugs than by bortezomib alone. Bortezomib arrested the cell cycles of three cell lines at the G2/M stage, decreased BCL2 mRNA expression, but did not affect MDR1 mRNA levels. The antiproliferative role of bortezomib was also confirmed in primary leukemia cells. CONCLUSION: Bortezomib is a promising potential therapy for acute leukemia, especially mdr1 drug-resistant leukemia.
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