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Mahendra, Seervi and Praveen K. , Sobhan and Krupa Ann , Mathew and Jeena , Joseph and Prakash , Rajappan Pillai and T. R., Santhoshkumar (2014) A high-throughput image-based screen for the identification of Bax/Bak-independent caspase activators against drug-resistant cancer cells. Apoptosis : an international journal on programmed cell death, 19 (1). pp. 269-284. ISSN 1573-675X

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Despite the use of new generation target specific drugs or combination treatments, drug-resistance caused by defective apoptosis signaling remains a major challenge in cancer treatment. A common apoptotic defect in drug-resistant tumor is the failure of cancer cells to undergo Bax/Bak-dependent mitochondrial permeabilization due to impaired signaling of Bcl-2 family proteins. Therefore, Bax and Bak-independent caspase-activating compounds appear to be effective in killing such tumor cells. An image-based cellular platform of caspase sensors in Bax and Bak deficient background allowed us to identify several potential Bax/Bak-independent caspase-activating compounds from a limited high-throughput compound screening. FRET-based caspase sensor probe targeted at the nucleus enabled accurate and automated segmentation, yielding a Z-value of 0.72. Some of the positive hits showed promising activity against drug-resistant human cancer cells expressing high levels of Bcl-2 or Bcl-xL. Using this approach, we describe thiolutin, CD437 and TPEN as the most potentially valuable drug candidates for addressing drug-resistance caused by aberrant expression of Bcl-2 family proteins in tumor cells. The screen also enables the quantification of multiparameter apoptotic events along with caspase activation in HTS manner in live mode, allowing characterization of non-classical apoptosis signaling.

Item Type: Article
Uncontrolled Keywords: High-throughput screeningDrug-resistanceApoptosisBcl-2 family proteinsCaspase
Subjects: Cancer Research
Depositing User: Central Library RGCB
Date Deposited: 16 Jan 2017 09:04
Last Modified: 16 Jan 2017 09:05
URI: http://rgcb.sciencecentral.in/id/eprint/160

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