Article

Putt, K.S. et al. Small molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy. Nat. Chem. Biol. 2, 543-550

Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
Nature Chemical Biology (Impact Factor: 13). 11/2006; 2(10):543-50. DOI: 10.1038/nchembio814
Source: PubMed

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.

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Available from: Jung-Taek Kwon, Apr 08, 2014
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    • "Several studies have shown a correlation between the ability of PAC-1 derivatives to activate procaspase-3 and the cytotoxicity against cancer cells lines [7] [8] [9] [10]. PAC derivatives like PAC-1a (DADH) that lack the ortho-hydroxy group are unable to chelate zinc and hence cannot activate procaspases, resulting in low cytotoxicity against cancer cells [10] [11]. Compounds that inhibit the activity of caspases have also been developed. "
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    • "After imaging, embryos were remounted (dorsal up) in 1.5% low melting point agarose (NuSieve) on a glass microscope slide. The Caspase-3 activator PAC-1 (procaspaseactivating compound 1; Tocris Bioscience; Putt et al., 2006) was dissolved in DMSO followed by embryo medium to a final concentration of 40 µm and pressure injected into the tectal ventricle, an approach previously shown to be able to target reagents to tectal cells (Leu and Schmidt, 2008). Embryos were placed individually in 500 µl embryo medium in a 24-well plate and incubated at RT for 3 h, sufficient time for PAC-1 to induce a high proportion of TUNEL-positive apoptotic cells in the retina and tectum (described in the next section). "
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    • "Conversely, pro-apoptotic modulating anti-cancer drugs are also being studied. Direct activation of executioner caspases like caspase-3 [89] or stimulation of cell death receptors involving the extrinsic apoptotic pathway has induced apoptosis and limited cell growth in lung cancer cell lines [90]. Lastly, gene replacement therapy to restore mutated cancer suppressor gene function is another promising strategy for cancer treatment. "
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