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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-10

AUTHORS

Karson S Putt, Grace W Chen, Jennifer M Pearson, Joseph S Sandhorst, Martin S Hoagland, Jung-Taek Kwon, Soon-Kyung Hwang, Hua Jin, Mona I Churchwell, Myung-Haing Cho, Daniel R Doerge, William G Helferich, Paul J Hergenrother

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. More... »

PAGES

543

Journal

TITLE

Nature Chemical Biology

ISSUE

10

VOLUME

2

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nchembio814

DOI

http://dx.doi.org/10.1038/nchembio814

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1016856142

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16936720


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