Abstract

Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, concentrations of procaspase-3 in certain cancerous cells are significantly higher than those in noncancerous controls. Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. We found that PAC-1 retarded the growth of tumors in three different mouse models of cancer, including two models in which PAC-1 was administered orally. PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3, a transformation that allows induction of apoptosis even in cells that have defective apoptotic machinery. The direct activation of executioner caspases is an anticancer strategy that may prove beneficial in treating the many cancers in which procaspase-3 concentrations are elevated.

1. Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
2. Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA.
3. Department of Food Science and Human Nutrition, University of Illinois, Urbana, Illinois 61801, USA.
4. Laboratory of Toxicology, College of Veterinary Medicine and Nano Systems Institute-National Core Research Center (NSI-NCRC), Seoul National University, Seoul 151-742, South Korea.
5. US Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72029, USA.

Correspondence to: Paul J Hergenrother^1,2 Email: hergenro@uiuc.edu

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