HMG-CoA Reductase Inhibitors Act Synergistically with UCN-01 Through RAS Inhibition

The primary objective of this study is to elucidate the mechanism by which the reagent UCN-01 induces apoptosis when administered to leukemia cells along with HmG-CoA reductase inhibitors, mainly the statins. In this study, we demonstrated that exposure of leukemia cell lines to lovastatin (20 uM, 18 hours) and UCN-01 (100 nM, 18 hours) resulted in mitochondria dysfunction, procaspase 3 and 9 cleavage, and PAW degradation along with marked cytochrome C release and apoptosis. Although similar molecular mechanisms have not yet been confirmed in other cancers, our hypothesis holds that enhanced apoptotic effects of UCN-01 are due in part to lovastatin's ability to block formation of geranylgeranylpyrophosphate and farnesylpyrophosphate by interfering with the rate-limiting step of the mevalonate pathway. Geranylgeranylpyrophosphate and farnesylpyrophosphate induce post-translational modifications in RAS that anchor the protein to the cell membrane so that it acts as a signal transducer to the nucleus, promoting cell proliferation.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Biomedical Engineering

Year dc:date.available

2006

Author dc:creator

• Khanna, Payal

Contributors dc:contributor

• Dr. Steven Grant

• farnesylpyrophosphate
• UCN-01
• geranylgeranylpyrophosphate
• mitochondria dysfunction
• apoptosis
• Biomedical Engineering and Bioengineering
• Engineering

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/953

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-1952