Abstract
Insight into the mechanisms of primary or acquired drug resistance of (hematological) malignancies is critical for the development of new treatment strategies. This review will focus on Bcl-2 and the mevalonate pathway as targets for reversal of drug resistance in multiple myeloma. The Bcl-2 protein is highly expressed in myeloma patients and in vitro studies have shown its role in the regulation of chemosensitivity, which makes Bcl-2 an attractive target for treatment. Statins are widely used for the treatment of hypercholesteremia. Several in vitro studies have shown that statins may also kill hematological malignant cells including myeloma cells. We found that lovastatin induced apoptosis in myeloma and lymphoma cells by inhibition of geranylgeranylation and subsequent down regulation of Mcl-1, probably the most important anti-apoptotic protein in myeloma. Phase 1 and 2 studies have been performed with Bcl-2 antisense oligonucleotides and high dose simvastatin in combination with chemotherapy in heavily pre-treated myeloma patients. Encouraging results from these studies may provide the framework for the future application of new treatment strategies for myeloma
Keywords: Multiple myeloma, drug resistance, apoptosis, proliferation, mevalonate pathway, geranylgeranylation, Bcl-2, Mcl-1
Current Pharmaceutical Design
Title: New Treatment Strategies for Multiple Myeloma by Targeting BCL-2 and the Mevalonate Pathway
Volume: 12 Issue: 3
Author(s): Niels W.C.J. van de Donk, Andries C. Bloem, Ellen v. d. Spek and Henk M. Lokhorst
Affiliation:
Keywords: Multiple myeloma, drug resistance, apoptosis, proliferation, mevalonate pathway, geranylgeranylation, Bcl-2, Mcl-1
Abstract: Insight into the mechanisms of primary or acquired drug resistance of (hematological) malignancies is critical for the development of new treatment strategies. This review will focus on Bcl-2 and the mevalonate pathway as targets for reversal of drug resistance in multiple myeloma. The Bcl-2 protein is highly expressed in myeloma patients and in vitro studies have shown its role in the regulation of chemosensitivity, which makes Bcl-2 an attractive target for treatment. Statins are widely used for the treatment of hypercholesteremia. Several in vitro studies have shown that statins may also kill hematological malignant cells including myeloma cells. We found that lovastatin induced apoptosis in myeloma and lymphoma cells by inhibition of geranylgeranylation and subsequent down regulation of Mcl-1, probably the most important anti-apoptotic protein in myeloma. Phase 1 and 2 studies have been performed with Bcl-2 antisense oligonucleotides and high dose simvastatin in combination with chemotherapy in heavily pre-treated myeloma patients. Encouraging results from these studies may provide the framework for the future application of new treatment strategies for myeloma
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van de Donk W.C.J. Niels, Bloem C. Andries, Spek v. d. Ellen and Lokhorst M. Henk, New Treatment Strategies for Multiple Myeloma by Targeting BCL-2 and the Mevalonate Pathway, Current Pharmaceutical Design 2006; 12 (3) . https://dx.doi.org/10.2174/138161206775201974
DOI https://dx.doi.org/10.2174/138161206775201974 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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