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M, Seervi and J, Joseph and P K , Sobhan and B C , Bhavya and T R , Santhoshkumar (2011) Essential requirement of cytochrome c release for caspase activation by procaspase-activating compound defined by cellular models. Cell death & disease, 2 (9). ISSN 2041-4889

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Mitochondrial cytochrome c (cyt. c) release and caspase activation are often impaired in tumors with Bcl-2 overexpression or Bax and Bak-defective status. Direct triggering of cell death downstream of Bax and Bak is an attractive strategy to kill such cancers. Small molecule compounds capable of direct caspase activation appear to be the best mode for killing such tumors. However, there is no precise model to screen such compounds. The currently employed cell-free systems possess the inherent drawback of lacking cellular contents and organelles that operate in integrating cell death signaling. We have developed highly refined cell-based approaches to validate direct caspase activation in cancer cells. Using this approach, we show that PAC-1 (first procaspase-activating compound), the first direct activator of procaspases identified in a cell-free system, in fact requires mitochondrial cyt. c release for triggering caspase activation similar to other antitumor agents. It can induce significant caspase activation and cell death in the absence of Bax and Bak, and in cells overexpressing Bcl-2 and Bcl-xL. This study for the first time defines precise criteria for the validation of direct caspase-activating compounds using specialized cellular models that is expected to accelerate the discovery of potential direct caspase activators.

Item Type: Article
Uncontrolled Keywords: cancer drug resistance, direct caspase activation, cytochrome c, apoptosis, mitochondria
Subjects: Cancer Research
Depositing User: Rgcb Library
Date Deposited: 18 May 2018 06:34
Last Modified: 18 May 2018 06:34
URI: http://rgcb.sciencecentral.in/id/eprint/589

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