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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib
Reshma Shringarpure1, Laurence Catley, Deepak Bhole
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Abstract:
The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM). Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To elucidate mechanisms of bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant SUDHL-4 and bortezomib-sensitive SUDHL-6 diffuse large B-cell lymphoma lines in response to bortezomib. At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in SUDHL-6 cells, but not in SUDHL-4 cells. We showed that overexpression of activating transcription factor 3 (ATF3), ATF4, ATF5, c-Jun, JunD and caspase-3 is associated with sensitivity to bortezomib-induced apoptosis, whereas overexpression of heat shock protein (HSP)27, HSP70, HSP90 and T-cell factor 4 is associated with bortezomib resistance.
Insights
Bortezomib effectively treats multiple myeloma, but resistance limits its use. This study identifies specific gene expression patterns linked to bortezomib sensitivity and resistance in lymphoma cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bortezomib is a proteasome inhibitor with clinical activity in multiple myeloma.
- Mechanisms of bortezomib-induced cytotoxicity and drug resistance remain incompletely understood.
- Resistance to bortezomib develops in most patients, limiting its efficacy.
Purpose of the Study:
- To elucidate the mechanisms underlying bortezomib resistance.
- To compare gene expression profiles of bortezomib-sensitive and resistant lymphoma cell lines.
- To identify molecular markers associated with bortezomib sensitivity and resistance.
Main Methods:
- Differential gene expression profiling of bortezomib-resistant (SUDHL-4) and sensitive (SUDHL-6) diffuse large B-cell lymphoma lines.
- Treatment of cell lines with bortezomib at concentrations inhibiting proteasome activity.
- Analysis of gene expression changes in response to bortezomib.
Main Results:
- Bortezomib induced apoptosis in sensitive SUDHL-6 cells but not in resistant SUDHL-4 cells.
- Overexpression of activating transcription factors (ATF3, ATF4, ATF5), c-Jun, JunD, and caspase-3 correlated with bortezomib sensitivity.
- Overexpression of heat shock proteins (HSP27, HSP70, HSP90) and T-cell factor 4 correlated with bortezomib resistance.
Conclusions:
- Specific gene expression profiles are associated with bortezomib sensitivity and resistance in diffuse large B-cell lymphoma.
- Identifying these molecular markers could aid in predicting treatment response and developing strategies to overcome bortezomib resistance.
