AI Article Synopsis
- Drug-resistance in cancer treatment is often due to defective apoptosis signaling, particularly the failure of Bax/Bak proteins to cause mitochondrial permeabilization, which limits the effectiveness of new targeted drugs.
- Using an innovative cellular platform with caspase sensors, researchers identified compounds that can activate caspases independently of Bax/Bak, potentially overcoming drug resistance in tumors.
- The study highlights thiolutin, CD437, and TPEN as promising candidates that could effectively target drug-resistant cancer cells concerning their aberrant Bcl-2 protein expression.
Article Abstract
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.
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| http://dx.doi.org/10.1007/s10495-013-0921-8 | DOI Listing |
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