Premium
Proteasome inhibitor bortezomib overcomes P‐gp‐mediated multidrug resistance in resistant leukemic cell lines
Author(s) -
ZHENG B.,
ZHOU R.,
GONG Y.,
YANG X.,
SHAN Q.
Publication year - 2012
Publication title -
international journal of laboratory hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.705
H-Index - 55
eISSN - 1751-553X
pISSN - 1751-5521
DOI - 10.1111/j.1751-553x.2011.01384.x
Subject(s) - bortezomib , daunorubicin , proteasome inhibitor , k562 cells , myeloid leukemia , leukemia , apoptosis , pharmacology , cell culture , cancer research , chemistry , medicine , biology , immunology , multiple myeloma , biochemistry , genetics
Summary 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.