Only in Titles

Search results for: ABT-263 Mechanisms: Bcl-2 family inhibitor

paperclip

#32911681   2020/09/08 To Up

Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells.

Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells. Cells were sampled before treatment, at 72 h of exposure, and after 10-day drug-free recovery from treatment. We observed transient alterations in the expression of stress response genes that were accompanied by corresponding changes in chromatin accessibility. Most of these changes returned to baseline after the recovery period. We also detected lasting alterations in methylation states and genome structure that suggest permanent changes in cell population composition. Using single-cell analyses, we identified 2350 genes significantly upregulated in navitoclax-resistant cells and derived an 18-gene navitoclax resistance signature. We assessed the navitoclax-response-predictive function of this signature in four additional TNBC cell lines in vitro and in silico in 619 cell lines treated with 251 different drugs. We observed a drug-specific predictive value in both experiments, suggesting that this signature could help guiding clinical biomarker studies involving navitoclax.
Michal Marczyk, Gauri A Patwardhan, Jun Zhao, Rihao Qu, Xiaotong Li, Vikram B Wali, Abhishek K Gupta, Manoj M Pillai, Yuval Kluger, Qin Yan, Christos Hatzis, Lajos Pusztai, Vignesh Gunasekharan

2778 related Products with: Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells.

100ul

Related Pathways

paperclip

#31430575   2019/08/17 To Up

Importance of Hypericin-Bcl2 interactions for biological effects at subcellular levels.

Hypericin (Hyp) is a naturally occurring compound used as photosensitizer in photodynamic therapy and diagnosis. Recently, we have shown that Hyp presence alone, without illumination, resulted in substantial biological effects at several sub-cellular levels. Hyp induced changes in cellular ultrastructure, mitochondria function and metabolism, and distribution of Bcl2 proteins in malignant and non-malignant cells. The molecular mechanisms that underlie Hyp light-independent effects are still elusive. We have hypothesized that Bcl2-Hyp interactions might be one possible mechanism. We performed molecular docking studies to determine the Hyp-Bcl2 interaction profile. Based on the interaction profiles small Bcl2 peptide segments were selected for further study. We designed small peptides corresponding to Bcl2 BH3 and BH1 domains and tested the binding of Hyp and Bcl2 known inhibitor, ABT263, to the peptides in computer modeling and in vitro binding studies. We employed endogenous tryptophan and tyrosine in the BH3 and BH1 peptides, respectively, and their fluorescent properties to show interaction with Hyp and ABT263. Overall, our results indicate that Hyp can interact with Bcl2 protein at its BH3-BH1 hydrophobic groove, and this interaction may trigger changes in intracellular distribution of Bcl2 proteins. In addition, our computer modeling results suggest that Hyp also interacts with other anti-apoptotic members of Bcl2 family similar to the known BH3 mimetics. Our findings are novel and might contribute to understanding Hyp light-independent effects. In addition, they may substantiate the therapeutic use of Hyp as a BH3 mimetic molecule to enhance other cancer treatments.
Katarina Stroffekova, Silvia Tomkova, Veronika Huntosova, Tibor Kozar

1614 related Products with: Importance of Hypericin-Bcl2 interactions for biological effects at subcellular levels.

50 ug 1 G1 ml100ul100ug Lyophilized 2x5L100ug Lyophilized200ul100ul3reactions2ml1 Set

Related Pathways

paperclip

#30905967   2019/03/25 To Up

Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer.

Genomic alterations in cancer cells result in vulnerabilities that clinicians can exploit using molecularly targeted drugs, guided by knowledge of the tumour genotype. However, the selective activity of these drugs exerts an evolutionary pressure on cancers that can result in the outgrowth of resistant clones. Use of rational drug combinations can overcome resistance to targeted drugs, but resistance may eventually develop to combinatorial therapies. We selected MAPK- and PI3K-pathway inhibition in colorectal cancer as a model system to dissect out mechanisms of resistance. We focused on these signalling pathways because they are frequently activated in colorectal tumours, have well-characterised mutations and are clinically relevant. By treating a panel of 47 human colorectal cancer cell lines with a combination of MEK- and PI3K-inhibitors, we observe a synergistic inhibition of growth in almost all cell lines. Cells with KRAS mutations are less sensitive to PI3K inhibition, but are particularly sensitive to the combined treatment. Colorectal cancer cell lines with inherent or acquired resistance to monotherapy do not show a synergistic response to the combination treatment. Cells that acquire resistance to an MEK-PI3K inhibitor combination treatment still respond to an ERK-PI3K inhibitor regimen, but subsequently also acquire resistance to this combination treatment. Importantly, the mechanisms of resistance to MEK and PI3K inhibitors observed, MEK1/2 mutation or loss of PTEN, are similar to those detected in the clinic. ERK inhibitors may have clinical utility in overcoming resistance to MEK inhibitor regimes; however, we find a recurrent active site mutation of ERK2 that drives resistance to ERK inhibitors in mono- or combined regimens, suggesting that resistance will remain a hurdle. Importantly, we find that the addition of low concentrations of the BCL2-family inhibitor navitoclax to the MEK-PI3K inhibitor regimen improves the synergistic interaction and blocks the acquisition of resistance.
Paul A Clarke, Toby Roe, Kate Swabey, Steve M Hobbs, Craig McAndrew, Kathy Tomlin, Isaac Westwood, Rosemary Burke, Robert van Montfort, Paul Workman

1255 related Products with: Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer.

100 μg25 100 100 μg1 mg5mg

Related Pathways

paperclip

#28035374   2016/12/30 To Up

Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: A rationale for combination with small molecular weight inhibitors.

DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities. Although efficacy of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side‑effect of the demethylating agent 5‑azacytidine in a patient with myelodysplastic syndrome. We investigated molecular mechanisms of decitabine (5‑Aza‑dC) antitumor activity in cHL using gene expression profiling followed by gene set enrichment analysis. We found that 5‑Aza‑dC inhibits growth of cHL cell lines at clinically relevant concentrations of 0.25‑2 µM. The antitumor effect of 5‑Aza‑dC was associated with induction of genes, which negatively regulate cell cycle progression (e.g. CDKN1A and GADD45A). Surprisingly, we also observed significant enrichment of pro‑survival pathways like MEK/ERK, JAK‑STAT and NF‑κB, as well as signatures comprising transcription‑activating genes. Among the upregulated pro‑survival genes were the anti‑apoptotic genes BCL2 and BCL2L1, as well as genes involved in transduction of growth and survival signals like STAT1, TLR7, CD40 and IL-6. We therefore analyzed whether interference with these pro‑survival pathways and genes would potentiate the antitumor effect of 5‑Aza‑dC. We could show that the BCL2/BCL2L1 inhibitor ABT263, the JAK‑STAT inhibitors fedratinib and SH‑4‑54, the AKT inhibitor KP372‑1, the NF‑κB inhibitor QNZ, as well as the bromodomain and extraterminal (BET) family proteins inhibitor JQ1 acted synergistically with 5‑Aza‑dC. We conclude that targeting of oncogenic pathways of cHL may improve efficacy of DNA-demethylating therapy in cHL.
Tatjana Maria Swerev, Thomas Wirth, Alexey Ushmorov

1768 related Products with: Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: A rationale for combination with small molecular weight inhibitors.

1 ml

Related Pathways

paperclip

#25289887   2014/10/07 To Up

MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis.

Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.
Robert N Booher, Harold Hatch, Brian M Dolinski, Thi Nguyen, Lauren Harmonay, Ali-Samer Al-Assaad, Mark Ayers, Michael Nebozhyn, Andrey Loboda, Heather A Hirsch, Theresa Zhang, Bin Shi, Carrie E Merkel, Minilik H Angagaw, Yaolin Wang, Brian J Long, Xianlu Q Lennon, Nathan Miselis, Vincenzo Pucci, James W Monahan, Junghoon Lee, Anna Georgieva Kondic, Eun Kyung Im, David Mauro, Rebecca Blanchard, Gary Gilliland, Stephen E Fawell, Leigh Zawel, Alwin G Schuller, Peter Strack

2112 related Products with: MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis.

3 mg50 ul2 Pieces/Box100 1 Set96T100 μg1 mg2 Pieces/Box96 assays100 ug5ug

Related Pathways