Date of Award

2007

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Robert Weiss

Abstract

Histone deacetylase inhibitors (HDACIs) mediate gene expression and chromatin assembly, and induce growth arrest and apoptosis of tumor cells, thus representing a new strategy for human cancer therapy. Changes in apoptosis signaling pathways and the effect on cell growth and cell-cycle arrest of a new HDACI, PXD101, on T-24 bladder cancer cells form the basis of this study. T-24 cells were incubated with PXD101 at varying concentrations and times, and viable cell count and proliferation curves were constructed. Cell cycle analysis was conducted with Fluorescent Activated Cell Sorting and changes in apoptosis signaling proteins that were previously found to be regulated by survivin-siRNA in T-24 cells were assessed by Western blot. Treatment of T-24 bladder cancer cells with the HDAC inhibitor PXD101 causes a profound decrease in cell growth and viability, a specific G2/M phase arrest and an increase in apoptotic cells populations. PXD101 treatment also causes changes in upstream mitochondrial apoptosis mediators, including TNFR1 and caspases 2 and 8, and downstream apoptosis mediators, such as caspase 3 and survivin. PXD101 treatment of tumor cells is associated with a profound decrease in survivin and caspases levels, and with an increase in TNFR1 protein levels, both changes indicative of induction of apoptosis. Therefore, the new HDACI PXD101, alone or in combination with inhibitors of other tumor relevant factors and chemotherapies with complementary mechanisms of action, shows promise for its use as a suitable new agent for bladder cancer treatment.

Comments

This is an Open Access Thesis.

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