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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma
W Wei-Lynn Wong1, James W Clendening, Anna Martirosyan
1Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (P = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM.
Insights
Statins can induce cancer cell death in multiple myeloma (MM). Genetic factors influence sensitivity, suggesting statins may offer targeted therapy for a subset of MM patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Statins are cholesterol-lowering drugs with demonstrated anti-cancer properties.
- Multiple myeloma (MM) is a plasma cell cancer with a poor prognosis.
- Statins can induce tumor-specific apoptosis in some cancer types.
Purpose of the Study:
- To investigate the sensitivity of multiple myeloma cell lines to statin-induced apoptosis.
- To identify mechanisms underlying statin sensitivity and resistance in MM.
- To explore the potential of statins as a targeted therapy for MM.
Main Methods:
- Testing 17 genetically distinct MM cell lines for sensitivity to lovastatin-induced apoptosis.
- Utilizing mevalonate and isoprenoid pyrophosphates to assess rescue from apoptosis.
- Performing gene expression profiling to analyze changes in Rho GTPase mRNA.
- Evaluating the impact of ectopic Rho/Ras protein expression on statin sensitivity.
Main Results:
- Approximately half of the tested MM cell lines were sensitive to statin-induced apoptosis.
- Sensitivity was linked to isoprenylation pathways, with rescue observed upon addition of mevalonate and specific isoprenoid pyrophosphates.
- Lovastatin exposure altered Rho GTPase mRNA expression in sensitive cells.
- Genetic abnormalities significantly correlated with statin sensitivity (P = 0.003).
Conclusions:
- Statin-induced apoptosis in MM is dependent on genetic factors and isoprenylation.
- Sensitivity is complex, involving multiple signaling cascades affected by statins.
- Statins show promise as a molecular targeted therapy for a subset of multiple myeloma patients.
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