Dataset Information

Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma.

ABSTRACT: The heterogeneous polyclonal nature of multiple myeloma complicates the identification of protein biomarkers predictive of drug response. In this study, a pharmacodynamic systems modeling approach was used to link in vitro bortezomib exposure and myeloma cell death. The exposure-response was integrated through a network of important protein biomarker dynamics activated by bortezomib in four myeloma cell lines. The pharmacodynamic models reasonably characterized the protein and myeloma cell dynamics simultaneously following bortezomib (20 nM) treatment. The models were used to identify differences in pathway dynamics across cell lines from model-estimated protein biomarker turnover parameters and global sensitivity analyses. Additionally, a statistical correlation analysis between drug sensitivity and model-fitted protein activation profiles (i.e., cumulative area under the protein expression-time curves) supported the identification of shared biomarkers associated with sensitivity differences among the cell lines. Both types of analysis identified similar important proteins associated with bortezomib pharmacodynamics, such as phosphorylated Nuclear Factor kappa-light-chain-enhancer of activated B cells (pNFkappaB), phosphorylated protein kinase B (pAKT), and caspase-8 (Cas 8).

SUBMITTER: Ramakrishnan V

PROVIDER: S-EPMC6430155 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma.

Ramakrishnan Vidya V Mager Donald E DE

CPT: pharmacometrics & systems pharmacology 20181204 3

The heterogeneous polyclonal nature of multiple myeloma complicates the identification of protein biomarkers predictive of drug response. In this study, a pharmacodynamic systems modeling approach was used to link in vitro bortezomib exposure and myeloma cell death. The exposure-response was integrated through a network of important protein biomarker dynamics activated by bortezomib in four myeloma cell lines. The pharmacodynamic models reasonably characterized the protein and myeloma cell dynam ...[more]

PMID: 30516019

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Project description:The MAGE-C1/CT7 encodes a cancer/testis antigen (CTA), is located on the chromosomal region Xq26-27 and is highly polymorphic in humans. MAGE-C1/CT7 is frequently expressed in multiple myeloma (MM) that may be a potential target for immunotherapy in this still incurable disease. MAGEC1/CT7 expression is restricted to malignant plasma cells and it has been suggested that MAGE-C1/CT7 might play a pathogenic role in MM; however, the exact function this protein in the pathophysiology of MM is not yet understood. Our objectives were (1) to clarify the role of MAGE-C1/CT7 in the control of cellular proliferation and cell cycle in myeloma and (2) to evaluate the impact of silencing MAGE-C1/CT7 on myeloma cells treated with bortezomib. Myeloma cell line SKO-007 was transduced for stable expression of shRNA-MAGE-C1/CT7. Downregulation of MAGE-C1/CT7 was confirmed by real time quantitative PCR and western blot. Functional assays included cell proliferation, cell invasion, cell cycle analysis and apoptosis. Western blot showed a 70-80% decrease in MAGE-C1/CT7 protein expression in inhibited cells (shRNA-MAGE-C1/CT7) when compared with controls. Functional assays did not indicate a difference in cell proliferation and DNA synthesis when inhibited cells were compared with controls. However, we found a decreased percentage of cells in the G2/M phase of the cell cycle among inhibited cells, but not in the controls (p<0.05). When myeloma cells were treated with bortezomib, we observed a 48% reduction of cells in the G2/M phase among inhibited cells while controls showed 13% (empty vector) and 9% (ineffective shRNA) reduction, respectively (p<0.01). Furthermore, inhibited cells treated with bortezomib showed an increased percentage of apoptotic cells (Annexin V+/PI-) in comparison with bortezomib-treated controls (p<0.001). We found that MAGE-C1/CT7 protects SKO-007 cells against bortezomib-induced apoptosis. Therefore, we could speculate that MAGE-C1/CT7 gene therapy could be a strategy for future therapies in MM, in particular in combination with proteasome inhibitors.

Dataset Information

Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma.

Publications

Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma.

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