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Updated: Jun 25, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
The effects of proteasome inhibitor bortezomib on a P-gp positive leukemia cell line K562/A02
1Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.
Abstract:
The aim of this study is to clarify the efficacy of proteasome inhibitor bortezomib to multidrug resistant (MDR) acute leukemia cells. We observed the effects of bortezomib on a P-glycoprotein (P-gp) positive leukemia line K562/A02. The results showed that bortezomib has significant effects on P-gp positive K562/A02 cells including cytotoxicity (48 h IC(50): 171.36 nM), induction of apoptosis (31.71 +/- 1.07% apoptotic cells after 24 h treatment at 100 nM), and inhibition of proteasome chymotrypsin-like activity (relative activity to untreated controls: 20.07 +/- 0.66% at 24 h with 10 nM bortezomib). These effects were lower than those observed in K562 cells (IC(50), percentage of apoptotic cells, relative chymotrypsin-like activity to untreated controls were 56.28 nM, 77.95 +/- 0.35%, 5.35 +/- 2.05% after the same treatments, respectively). No synergy between daunorubicin and bortezomib was shown in the killing of K562/A02 cells (synergistic ratios were <1). P-gp expression levels did not decrease in K562/A02 cells after bortezomib treatment. Pretreatment with bortezomib does not improve the intracellular anthracycline concentration in K562/A02 cells. Bortezomib shows a promising effect for the treatment of refractory/relapsed leukemia, but it does not improve the effect of anthracycline to MDR leukemia cells.
Insights
Proteasome inhibitor bortezomib shows efficacy against multidrug-resistant (MDR) leukemia cells by inducing apoptosis and inhibiting proteasome activity. However, it does not enhance anthracycline effects in these resistant cells.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a significant challenge in acute leukemia treatment.
- Proteasome inhibitors, like bortezomib, are potential therapeutic agents for leukemia.
- P-glycoprotein (P-gp) is a key efflux pump contributing to MDR.
Purpose of the Study:
- To evaluate the efficacy of bortezomib in multidrug-resistant (MDR) acute leukemia cells.
- To investigate bortezomib's effects on P-glycoprotein (P-gp) positive leukemia cells.
- To determine if bortezomib can overcome MDR or synergize with anthracyclines.
Main Methods:
- Assessed cytotoxicity, apoptosis induction, and proteasome chymotrypsin-like activity inhibition of bortezomib in K562/A02 (MDR) and K562 (sensitive) cell lines.
- Evaluated the synergistic effect of bortezomib with daunorubicin.
- Measured P-gp expression levels and intracellular anthracycline concentration after bortezomib treatment.
Main Results:
- Bortezomib demonstrated significant cytotoxicity, apoptosis induction, and proteasome inhibition in K562/A02 cells, though less potent than in K562 cells.
- No synergistic effect was observed between bortezomib and daunorubicin in K562/A02 cells.
- Bortezomib treatment did not reduce P-gp expression or enhance intracellular anthracycline uptake in MDR cells.
Conclusions:
- Bortezomib exhibits promising activity against refractory/relapsed leukemia.
- Bortezomib does not enhance the efficacy of anthracyclines in MDR leukemia cells.
- The mechanism of bortezomib's action in MDR cells warrants further investigation.
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