Increased ABCB1 expression in TP-110-resistant RPMI-8226 cells
Masatomi Iijima1, Isao Momose, Daishiro Ikeda
1Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Shizuoka, Japan. iijimam@bikaken.or.jp
Bioscience, Biotechnology, and Biochemistry
|September 14, 2010
Summary
TP-110, a novel proteasome inhibitor, shows potent growth inhibition in multiple myeloma cells. Resistance mechanisms involve elevated P-glycoprotein (MDR1), a drug-efflux pump, which can be overcome by verapamil.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- TP-110 is a novel proteasome inhibitor with potent anti-myeloma activity.
- Understanding resistance mechanisms is crucial for enhancing therapeutic efficacy.
Purpose of the Study:
- To establish and characterize TP-110-resistant human multiple myeloma cells (RPMI-8226/TP-110).
- To elucidate the molecular mechanisms underlying TP-110 resistance.
Main Methods:
- Development of TP-110-resistant cell line (RPMI-8226/TP-110).
- Assessment of cytotoxicity and cross-resistance to various chemotherapeutic agents.
- Analysis of P-glycoprotein (MDR1/ABCB1) expression using DNA microarray and RT-PCR.
- Evaluation of MDR1 inhibitor (verapamil) efficacy in overcoming resistance.
Main Results:
- RPMI-8226/TP-110 cells exhibited a 10-fold higher IC₅₀ for TP-110 compared to parental cells.
- Cross-resistance was observed with other proteasome inhibitors and cytotoxic drugs (doxorubicin, etoposide, taxol, vincristine).
- Elevated expression of P-glycoprotein (MDR1/ABCB1) was confirmed in resistant cells.
- Verapamil effectively reversed TP-110 resistance in RPMI-8226/TP-110 cells.
Conclusions:
- TP-110 resistance in RPMI-8226 cells is mediated by the upregulation of P-glycoprotein (MDR1).
- P-glycoprotein acts as a drug-efflux pump, contributing to multi-drug resistance.
- Targeting P-glycoprotein may be a viable strategy to overcome TP-110 resistance in multiple myeloma.
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