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Proteasome inhibitor bortezomib overcomes P-gp-mediated multidrug resistance in resistant leukemic cell lines

B Zheng1, R Zhou, Y Gong

  • 1Department of Hematology and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.

International Journal of Laboratory Hematology
|December 8, 2011
PubMed
Abstract

Insights

Bortezomib effectively combats acute myeloid leukemia cells, including drug-resistant types, by inhibiting growth and inducing apoptosis. Combination therapy with daunorubicin shows synergistic effects, enhancing treatment potential for resistant leukemia.

Area of Science:

  • Hematology
  • Oncology
  • Pharmacology

Background:

  • Investigating bortezomib and daunorubicin (DNR) efficacy in drug-resistant and sensitive leukemia cell lines (K562/MDR1, K562/A02, K562).
  • Assessing treatment effects on primary acute myeloid leukemia cells.

Purpose of the Study:

  • To evaluate bortezomib, alone and with DNR, against various leukemia models.
  • To determine the impact on cell proliferation, cell cycle, apoptosis, and gene expression (MDR1/BCL2).

Main Methods:

  • Exposure of cell lines and primary cells to bortezomib, DNR, and their combination.
  • Analysis of cell proliferation, cell cycle progression, apoptosis rates.
  • Quantification of MDR1 and BCL2 mRNA expression.

Main Results:

  • Bortezomib demonstrated potent growth inhibition and apoptosis induction across tested cell lines.
  • The combination of bortezomib and DNR exhibited synergistic antiproliferative effects and enhanced apoptosis.
  • Bortezomib induced G2/M cell cycle arrest and decreased BCL2 mRNA, without altering MDR1 mRNA levels.
  • Verapamil affected DNR but not bortezomib's efficacy in resistant cells.
  • Bortezomib's antiproliferative activity was confirmed in primary leukemia cells.

Conclusions:

  • Bortezomib shows significant promise as a therapeutic agent for acute leukemia.
  • It is particularly effective against mdr1 drug-resistant leukemia, offering a potential new treatment avenue.

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