Defense Date

2006

Document Type

Thesis

Degree Name

Master of Science

Department

Biomedical Engineering

First Advisor

Dr. Steven Grant

Abstract

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.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2008

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