Cytoskeleton inhibitors combined with TRAIL induce apoptosis in HeLa carcinoma cells overexpressing antiapoptotic protein Bcl-2

Gasparian, Marine E.; Domnina, L. V.; Ivanova, O. Yu.; Izyumov, D. S.; Lomakin, Alexis J.; Попова, Е. Н.; Yagolovich, Anne V.; Pletjushkina, Olga Yu.; Долгих, Д. А.; Chernyak, Boris V.

doi:10.1134/s000629790803019x

Cited by 3 publications

(4 citation statements)

References 25 publications

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“…4). We have shown earlier that the inhibitor of microtubules, taxol and the inhibitor of actin microfilaments, cytochalasin D enhanced efficiency of TRAIL and allow it to overcome antiapoptotic effect of Bcl-2 [20]. All the DR5-selective TRAIL variants did not lose the capacity to break Bcl-2 block in combination with the inhibitors of cytoskeleton (Fig.…”

Section: Generation Of New Dr5-selective Trail Mutant Variantsmentioning

confidence: 72%

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Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5

et al. 2009

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TRAIL (tumor necrosis factor (TNF) related apoptosis-inducing ligand) has been introduced as an extrinsic pathway inducer of apoptosis that does not have the toxicities of Fas and TNF. However, the therapeutic potential of TRAIL is limited because of many primary tumor cells are resistant to TRAIL. Despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity and efficiency. A major reason likely lies in the complexity of the interaction of TRAIL with its five receptors, of which only two DR4 and DR5 are death receptors. Binding of TRAIL with decoy receptors DcR1 and DcR2 or soluble receptor osteoprotegerin (OPG) fail to induce apoptosis. Here we describe design and expression in Escherichia coli of DR5-selective TRAIL variants DR5-A and DR5-B. The measurements of dissociation constants of these mutants with all five receptors show that they practically do not interact with DR4 and DcR1 and have highly reduced affinity to DcR2 and OPG receptors. These mutants are more effective than wild type TRAIL in induction of apoptosis in different cancer cell lines. In combination with the drugs targeted to cytoskeleton (taxol, cytochalasin D) the mutants of TRAIL induced apoptosis in resistant Hela cells overexpressing Bcl-2. The novel highly selective and effective DR5-A and DR5-B TRAIL variants will be useful in studies on the role of different receptors in TRAIL-induced apoptosis in sensitive and resistant cell lines.

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Section: Generation Of New Dr5-selective Trail Mutant Variantsmentioning

confidence: 72%

“…In our previous studies we have demonstrated that expression of Bcl-2 blocks TRAIL-induced release of cytochrome c from mitochondria into cytosol and apoptosis in Hela cells [20]. No one of the DR5-selective TRAIL variants could overcome this block of apoptosis (Fig.…”

Section: Generation Of New Dr5-selective Trail Mutant Variantsmentioning

confidence: 93%

Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5

et al. 2009

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“…While only few compounds contributed to tubulin enrichment (Table ), the HTS actives included antimitotic agent grisofulvin and several colchicine derivatives, suggesting that this correlation is authentic. Indeed, microtubule-targeted agents nocodazole and paclitaxel are reported to sensitize cancer cells to TRAIL. ,, The enrichment analysis also identified ABL, Src, FAK, PAK1, and CDK5, kinase targets linked to cytoskeleton arrangements and tubulin stability (Figure ), but these targets proved less fruitful. The Src, ABL, and CDK5 inhibitors primarily inhibited GSK3, and GSK3 could not be discounted adequately.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, microtubule-targeted agents nocodazole and paclitaxel are reported to sensitize cancer cells to TRAIL. 55,67,56 The enrichment analysis also identified ABL, Src, FAK, PAK1, and CDK5, kinase targets linked to cytoskeleton arrangements and tubulin stability (Figure 3), but these targets proved less fruitful. The Src, ABL, and CDK5 inhibitors primarily inhibited GSK3, and GSK3 could not be discounted adequately.…”

Section: ■ Resultsmentioning

confidence: 99%

Enrichment Analysis for Discovering Biological Associations in Phenotypic Screens

Polyakov

Moorcroft

Drawid

2014

J. Chem. Inf. Model.

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A phenotypic screen (PS) is used to identify compounds causing a desired phenotype in a complex biological system where mechanisms and targets are largely unknown. Deconvoluting the mechanism of action of actives and identification of relevant targets and pathways remains a formidable challenge. Current methods fail to use the rich information available regarding compounds and their targets in a systematic way for this deconvolution. We have developed an enrichment analysis algorithm to identify targets associated with the desired phenotype in a rigorous data-driven manner using actives and hundreds of thousands of inactives in a PS, as well as results of thousands of available legacy target-based screens in an institution. Our method quantifies association between the PS and targets while reducing sampling bias, which leads to identification of novel targets, additional chemical matter, and appropriate assays. Its use is illustrated using two examples from our laboratories: TRAIL and DNA fragmentation. Enrichment analysis of these PSs is discussed using both biological pathway analysis and known cell biology to demonstrate the value of our method. We believe this enrichment analysis method is an indispensable tool for the analysis of PSs.

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Breast Cancer Proteome Takes More Than Two to Tango on TRAIL: Beat Them at Their Own Game

et al. 2012

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Breast carcinogenesis is a multidimensional disease that has resisted drug-related solutions to date because of heterogeneity, disorganized spatiotemporal behavior of signal transduction cascades, cell cycle checkpoints, cell transition, plasticity, and impaired pro-apoptotic response. These synchronized oncogenic events, including protein-protein interaction, transcriptional-regulatory, and signaling networks, trigger genomic and transcriptional disturbances in TRAIL-mediated signaling network neighborhoods. Therefore, tumor cells often acquire the ability to escape death by suppressing cell death pathways that normally function to eliminate damaged and harmful cells. This review describes the TRAIL-mediated cell death signaling pathways, the interactions between these pathways, and the ways in which these pathways are deregulated in breast cancer.

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Cytoskeleton inhibitors combined with TRAIL induce apoptosis in HeLa carcinoma cells overexpressing antiapoptotic protein Bcl-2

Cited by 3 publications

References 25 publications

Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5

Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5

Enrichment Analysis for Discovering Biological Associations in Phenotypic Screens

Breast Cancer Proteome Takes More Than Two to Tango on TRAIL: Beat Them at Their Own Game

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