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Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy

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Authors
Putt, Karson S; Chen, Grace W; Pearson, Jennifer M; Sandhorst, Joseph S; Hoagland, Martin S; Kwon, Jung-Taek; Hwang, Soon-Kyung; Jin, Hua; Churchwell, Mona I; Cho, Myung-Haing; Doerge, Daniel R; Helferich, Daniel R; Hergenrother, Paul J
Issue Date
2006-08-27
Publisher
Nature Publishing Group
Citation
Nat. Chem. Biol. 2, 543-550 (2006)
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.
ISSN
1552-4450
Language
English
URI
http://hdl.handle.net/10371/6910
DOI
https://doi.org/10.1038/nchembio814
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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