Defense Date

2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Anatomy & Neurobiology

First Advisor

Dr. Paul Dent

Abstract

Our laboratory is primarily interested in novel pharmacological intervention of cell proliferation and survival pathways expressed in various types of cancer. These cyto-protective pathways can be activated in response to growth factor stimulation, toxic insult and radiation. In our studies, we utilized novel drug combinations with and without radiation to enhance breast & prostate tumor cell death both in vitro and in vivo. Previous studies from our group have shown that UCN-01 and MEK1/2 inhibitors interact to cause tumor cell death in transformed cell lines in vitro. We extended this observation to an in vivo animal model system using the estrogen dependent breast cell carcinoma line MCF-7 and the estrogen independent breast cell carcinoma line MDA-MB-231. This drug combination was shown to profoundly reduce tumor cell proliferation in vivo and also exhibited the ability to significantly reduce ex-vivo tumor cell colony formation 30 days after cessation of the combination drug treatment. In addition, tumor cell death coincided with decreased ERK112 phosphorylation, reduced immunoreactivity of Ki67 and CD31. Overall, these studies demonstrate that UCN-01 and MEK112 inhibitors have the potential to suppress mammary tumor growth in vivo which is independent of p53 status, estrogen dependency, caspase-3 levels or oncogenic K-RAS expression. In our LnCap prostate carcinoma cell studies we demonstrated the impact of hCG and lovastatin in combination with ionizing radiation to radiosensitize and enhance tumor cell lethality. This enhancement was attributed to the hCG-induced activation of ERBB1 via a GPCR, MEK112 and metalloprotease dependent paracrine mechanism which was further enhanced by radiation. This enhanced cell killing effect was shown to involve prolonged activation of PARP1 which could be suppressed by inhibition of ERBB1, MEKl , PI3 kinase or PARP1. Therefore, the combination of hCG, lovastatin and radiation may represent a novel approach to kill prostate cancer cells and potential new therapy.

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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