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Bortezomib resistance in a myeloma cell line is associated to PSMβ5 overexpression and polyploidy
Patricia Balsas1, Patricia Galán-Malo, Isabel Marzo
1Department of de Bioquimica, Biologia Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain.
Abstract:
Bortezomib is a proteasome inhibitor important to the therapy of multiple myeloma (MM), though a number of patients show resistance to this drug. To study the cellular basis of this resistance we have generated a MM cell line displaying enhanced (5-6-fold) resistance to bortezomib by serial cultivation of RPMI 8226 cells with increasing concentrations of this drug. Bortezomib-resistant cells (8226/7B) became bigger in size than parental cells and nearly doubled the amount of DNA per cell, evolving from hypotriploidy to near-tetraploidy. 8226/7B displayed lowered Noxa accumulation and reduced caspase-3 activation in response to bortezomib. Resistant 8226/7B cells overexpressed the PSMβ5 proteasome subunit, the molecular target of bortezomib, both at the mRNA and protein level. No mutations were detected in the PSMβ5 gene. Bortezomib-resistant cells were roughly as sensitive as parental cells to other chemotherapeutic drugs, including doxorubicin, melphalan, vincristine, BMS-214662 and BMS-345541. 8226/7B cells showed partial and high cross-resistance to the proteasome inhibitors epoxomicin and MG-132, respectively. Co-treatment with the histone deacetylase inhibitor trichostatin A (TSA) potentiated bortezomib-induced apoptosis in parental RPMI 8226 cells but did not revert bortezomib resistance in 8226/7B cells. Therefore, treatment of bortezomib-refractory myeloma with drugs targeting molecular structures other than proteasome seems to be the more suitable therapeutic strategy to overcome bortezomib resistance.
Insights
Researchers developed bortezomib-resistant multiple myeloma cells (8226/7B) to study drug resistance mechanisms. These cells overexpressed the proteasome subunit PSMβ5, indicating a potential target for overcoming resistance in multiple myeloma therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bortezomib is a key proteasome inhibitor for multiple myeloma (MM).
- Drug resistance limits bortezomib efficacy in a subset of MM patients.
- Understanding resistance mechanisms is crucial for improving MM treatment.
Purpose of the Study:
- To investigate the cellular basis of bortezomib resistance in multiple myeloma.
- To generate and characterize a bortezomib-resistant MM cell line.
- To identify potential strategies for overcoming bortezomib resistance.
Main Methods:
- Generated a bortezomib-resistant MM cell line (8226/7B) through serial drug cultivation.
- Analyzed cell size, DNA content, Noxa accumulation, and caspase-3 activation.
- Assessed PSMβ5 proteasome subunit expression (mRNA and protein) and gene mutations.
- Evaluated cross-resistance to other chemotherapeutics and proteasome inhibitors.
- Investigated the effect of trichostatin A (TSA) co-treatment.
Main Results:
- The 8226/7B cell line exhibited 5-6 fold resistance to bortezomib.
- Resistant cells showed increased size, near-tetraploidy, reduced Noxa accumulation, and decreased caspase-3 activation.
- PSMβ5 proteasome subunit was overexpressed at mRNA and protein levels without mutations.
- 8226/7B cells displayed cross-resistance to other proteasome inhibitors but not to other chemotherapeutics.
- TSA potentiated bortezomib-induced apoptosis in parental cells but not in resistant cells.
Conclusions:
- Overexpression of the PSMβ5 proteasome subunit is a key mechanism of bortezomib resistance in this MM model.
- Targeting molecular structures other than the proteasome may be a viable strategy for bortezomib-refractory myeloma.
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