Simvastatin enhances the efficacy of Bcr-Abl tyrosine kinase inhibitor nilotinib in chronic myeloid leukemia.

• Main Author: Koh, Yanqing.
• Other Authors: School of Biological Sciences
• Format: Final Year Project
• Language: English
• Published: 2011
• Subjects: DRNTU::Science::Biological sciences::Biochemistry
• Online Access: http://hdl.handle.net/10356/45121
• Institution: Nanyang Technological University

One of the major challenges in treatment of chronic myeloid leukemia (CML) is the continual emergence of new resistance to single agent Bcr-Abl tyrosine kinase inhibitors (TKIs). A strategy to cope with cancer progression is by targeting multiple levels of signaling pathways downstream of Bcr-Abl kinase such as Ras and Rho pathways. The Ras pathway, in particular, plays an important role in promoting proliferation and survival in many cancers. The biological function of Ras and Rho is dependent on prenylation. Statins are inhibitors of HMG-CoA reductase and are able to decrease biosynthesis of prenylation substrates. In this study, we aimed to investigate the efficacy of the combination of a Bcr-Abl TKI, nilotinib and simvastatin in inhibiting proliferation and inducing apoptosis in CML cell lines as well as its effects on the clonogenicity of primary CML cells. We determined that nilotinib and simvastatin in combination showed synergy in inhibiting proliferation and induced enhanced apoptosis in CML cell lines. Synergy in inhibiting proliferation was also observed in primary CML cells. Finally, we verified enhanced apoptosis was due to reduction in prenylation substrates. Therefore, we propose that the combination of these two clinically available drugs has potential to overcome clinical resistance in CML.