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


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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    ABSTRACT: Dysregulation of apoptotic cell death is observed in a large number of pathological conditions. As caspases are central enzymes in the regulation of apoptosis, a large number of procaspase-activating compounds (PAC-1 derivatives) and inhibitors (isatin derivatives) have been developed. Matrix metalloproteinases (MMPs) have been shown to have a dual role in apoptosis. Hence compounds that either activate or inhibit caspases should ideally not affect MMPs. As many PAC-1 derivatives contain a zinc chelating ortho-hydroxy N-acyl hydrazone moiety and isatin derivatives has two carbonyl groups on the indole core, it was of interest to determine to which extent these compounds can inhibit MMPs.
    Full-text · Article · Jul 2014 · Biochimica et Biophysica Acta (BBA) - General Subjects
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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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    ABSTRACT: In addition to being critical for apoptosis, components of the apoptotic pathway, such as caspases, are involved in other physiological processes in many types of cells, including neurons. However, very little is known about their role in dynamic, nonphysically destructive processes, such as axonal arborization and synaptogenesis. We show that caspases were locally active in vivo at the branch points of young, dynamic retinal ganglion cell axonal arbors but not in the cell body or in stable mature arbors. Caspase activation, dependent on Caspase-3, Caspase-9, and p38 mitogen-activated protein kinase (MAPK), rapidly increased at branch points corresponding with branch tip addition. Time-lapse imaging revealed that knockdown of Caspase-3 and Caspase-9 led to more stable arbors and presynaptic sites. Genetic analysis showed that Caspase-3, Caspase-9, and p38 MAPK interacted with Slit1a-Robo2 signaling, suggesting that localized activation of caspases lie downstream of a ligand receptor system, acting as key promoters of axonal branch tip and synaptic dynamics to restrict arbor growth in vivo in the central nervous system.
    Full-text · Article · Nov 2013 · The Journal of Cell Biology
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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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    ABSTRACT: The influence of mitochondria in human health and disease is a rapidly expanding topic in the scientific literature due to their integral roles in cellular death and survival. Mitochondrial biology and alterations in function were first linked to cancer in the 1920s with the discovery of the Warburg effect. The utilization of aerobic glycolysis in ATP synthesis was the first of many observations of metabolic reprogramming in cancer. Mitochondrial dysfunction in cancer has expanded to include defects in mitochondrial genomics and biogenesis, apoptotic signaling and mitochondrial dynamics. This review will focus on the role of mitochondria and their influence on cancer initiation, progression and treatment in the lung.
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