English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Apoptosis is a complex pathway regulated by the concerted action of multiplepro- and anti-apoptotic molecules. The intrinsic (mitochondrial) pathway ofapoptosis is governed up-stream of mitochondria, by the family of Bcl-2proteins, and down-stream of mitochondria, by low-probability events, such asapoptosome formation, and by feedback circuits involving caspases and inhibitorof apoptosis proteins (IAPs), such as XIAP. All these regulatory mechanismsensure that cells only commit to death once a threshold of damage has beenreached and the anti-apoptotic reserve of the cell is overcome. As cancer cellsare invariably exposed to strong intracellular and extracellular stressstimuli, they are particularly reliant on the expression of anti-apoptoticproteins. Hence, many cancer cells undergo apoptosis when exposed to agentsthat inhibit anti-apoptotic Bcl-2 molecules, such as BH3 mimetics, while normalcells remain relatively insensitive to single agent treatments with the sameclass of molecules. Targeting different proteins within the apoptotic networkwith combinatorial treatment approaches often achieves even greaterspecificity. This led us to investigate the sensitivity of leukemia andlymphoma cells to a pro-apoptotic action of a BH3 mimetic combined with a smallmolecule inhibitor of XIAP. Using computational probabilistic model ofapoptotic pathway, verified by experimental results from human leukemia andlymphoma cell lines, we show that inhibition of XIAP has a non-linear effect onsensitization towards apoptosis induced by the BH3 mimetic HA14-1. This studyjustifies further ex vivo and animal studies on the potential of the treatmentof leukemia and lymphoma with a combination of BH3 mimetics and XIAPinhibitors.

Nonlinear regulation of commitment to apoptosis by simultaneous inhibition of Bcl-2 and XIAP in leukemia and lymphoma cells