Small molecule activators of procaspase-3 as an anticancer strategy

Peterson, Quinn P.

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https://hdl.handle.net/2142/29573 Copy

Description

Title

Small molecule activators of procaspase-3 as an anticancer strategy

Author(s)

Peterson, Quinn P.

Issue Date

2012-02-01T00:56:11Z

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J.

Doctoral Committee Chair(s)

Hergenrother, Paul J.

Committee Member(s)

• van der Donk, Wilfred A.
• Fan, Timothy M.
• Shapiro, David J.

Department of Study

Biochemistry

Discipline

Biochemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• procaspase-3
• zinc
• anticancer
• small-molecule

Abstract

Although general anti-proliferative agents that induce death in all rapidly dividing cell types remain the backbone of many chemotherapeutic regimens, recent advances have suggested that “personalized” anticancer strategies hold considerable promise. In personalized medicine, a detailed understanding of the molecular aberrations in the cell is utilized to select a drug with an appropriate mechanism of action. The potential for such strategies has been powerfully demonstrated for cancers that have translocations, mutations, or aberrant expression levels of key proteins. The apoptotic protein procaspase-3 has been shown to be upregulated in a variety of cancer cell types and plays a pivotal role in the execution of apoptosis. As such, the reactivation of the apoptotic cascade through small molecule activators of procaspase-3 is an attractive anticancer strategy. In 2006, the discovery of the first small molecule activator of procaspase-3 (PAC-1) was reported by the Hergenrother laboratory. The studies described herein build on that discovery to expand our understanding of the potential and promise of small molecule activators of procaspase-3 in the treatment of cancer. Characterization of the mechanism of action of PAC-1 in vitro and in cell culture reveals that PAC-1 activates procaspase-3 through the relief of zinc-mediated inhibition of procaspase-3 resulting in the induction of apoptosis. In vivo studies in mice and dogs further demonstrate the feasibility and tolerability of procaspase-3 activators in the treatment of cancer. Canine clinical studies show that small molecules in the PAC-1 class are capable of inducing tumor regression in dogs with lymphoma. These results highlight the importance that zinc plays in the regulation of caspase activity and the induction of apoptosis. Studies that characterize the interaction between procaspase-3 and zinc are presented.

Graduation Semester

2011-12

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http://hdl.handle.net/2142/29573

Copyright and License Information

Copyright 2011 Quinn P. Peterson

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