Date of Completion

2-27-2013

Embargo Period

8-25-2013

Keywords

HDAC, tropolone, cancer, SAHA, hinokitiol, isoform-selective inhibitor

Major Advisor

Amy C. Anderson

Associate Advisor

Dennis L. Wright

Associate Advisor

Charles A. Giardina

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Cancer is the second leading cause of death in the United States. Inhibitors that target key enzymes involved in epigenetic alterations, particularly histone deacetylases (HDACs), are garnering interest in cancer research because of their unique ability to reversibly induce terminal differentiation of transformed cells by influencing chromatin structure. Through an in-house collaborative effort, derivatives of hinokitiol, a troplone-related non-benzenoid aromatic compound, are being synthesized and characterized by the Wright and Anderson laboratories as HDAC inhibitors (HDACi). Given the novelty of these tropolones as antineoplastic agents, a number of biochemical and functional studies were conducted in order to develop tropolones as isoform-selective HDACi with potent antitumor properties. These studies include: (1) Elucidation of HDAC enzymatic activity and inhibition, (2) Comparative analyses of antiproliferative effects in a panel of normal dermal fibroblasts, solid tumor and hematological cell lines, (3) Evaluation of induction and mechanisms of cell death by apoptosis, (4) Assessment of histone and tubulin modulation, and (5) Investigation of specific gene expression. Ultimately, the knowledge garnered from these studies will be used to develop a new library of isoform-selective HDAC inhibitors with a wider therapeutic index for the treatment of both solid tumors and hematological malignancies.

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