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Molecular mechanisms of bortezomib resistant adenocarcinoma cells
- Source :
- PLoS ONE, Vol 6, Iss 12, p e27996 (2011), PLoS ONE
- Publication Year :
- 2011
- Publisher :
- Public Library of Science (PLoS), 2011.
-
Abstract
- Bortezomib (Velcade™) is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM). Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ∼30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response.
- Subjects :
- Cancer Treatment
lcsh:Medicine
Biochemistry
Plasma Cell Disorders
Bortezomib
chemistry.chemical_compound
0302 clinical medicine
hemic and lymphatic diseases
Cytotoxic T cell
lcsh:Science
Multiple myeloma
0303 health sciences
Multidisciplinary
Hematology
Boronic Acids
3. Good health
Oncology
030220 oncology & carcinogenesis
Pyrazines
Medicine
Multiple Myeloma
medicine.drug
Research Article
Biotechnology
Drugs and Devices
Drug Research and Development
Blotting, Western
Antineoplastic Agents
Enzyme-Linked Immunosorbent Assay
Cycloheximide
Biology
Adenocarcinoma
03 medical and health sciences
Cell Line, Tumor
Chemical Biology
medicine
Humans
030304 developmental biology
lcsh:R
Chemotherapy and Drug Treatment
medicine.disease
Carfilzomib
Molecular biology
chemistry
Proteasome
Cell culture
Small Molecules
Drug Resistance, Neoplasm
Proteasome inhibitor
Cancer research
lcsh:Q
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 6
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....e4ecef4f6183056b7114077782937a0f