Computational modelling of LY303511 and TRAIL-induced apoptosis suggests dynamic regulation of cFLIP.

Motivation: TRAIL has been widely studied for the ability to kill cancer cells selectively, but its clinical usefulness has been hindered by the development of resistance. Multiple compounds have been identified that sensitize cancer cells to TRAIL-induced apoptosis. The drug LY303511 (LY30), combined with TRAIL, caused synergistic (greater than additive) killing of multiple cancer cell lines.

The three Rs along the TRAIL: resistance, re-sensitization and reactive oxygen species (ROS).

Ligation of the Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors has been associated with cancer specific apoptotic execution in a number of model systems. This has generated tremendous interest in the use of TRAIL as a potential therapeutic modality. However, recent evidence indicates that resistance to TRAIL might present with a therapeutic challenge.

Knock down of heat shock protein 27 (HspB1) induces degradation of several putative client proteins.

Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27.

TRAILing death in cancer.

The observation that certain types of cancer express death receptors on their cell surface has triggered heightened interest in exploring the potential of receptor ligation as a novel anti-cancer modality, and since the expression is somewhat restricted to cancer cells the therapeutic implications are very promising. One such death receptor ligand belonging to the tumor necrosis receptor (TNF) superfamily, TNF-related apoptosis-inducing ligand (TRAIL), has been in the limelight as a tumor selective molecule that transmits death signal via ligation to its receptors (TRAIL-R1 and TRAIL-R2 or death receptors 4 and 5; DR4 and DR5). Interestingly, TRAIL-induced apoptosis exhibits hallmarks of extrinsic as well as intrinsic death pathways, and, therefore, is subject to regulation both at the cell surface receptor level as well as more downstream at the post-mitochondrial level.

Cytotoxic effects induced by oxidative stress in cultured mammalian cells and protection provided by Hsp27 expression.

There is currently great interest in the development of methods to analyze intracellular redox state and the cellular damages generated by oxidative stress. General methods for analyzing reactive oxygen species and glutathione level are presented together with more recently developed protocols to analyze the consequences of oxidative stress on the oxidation of macromolecules. Finally, techniques to study modalities of constitutive expression of Hsp27 in mammalian cells are considered as well as methods used to determine the protective activity of this small heat shock protein against the deleterious effects induced by oxidative stress.