Targeting the mitotic kinase NEK2 enhances CDK4/6 inhibitor efficacy by potentiating genome instability

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108196 - 108196

Published: Jan. 1, 2025

Language: Английский

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Systematic Comparison of FBS and Medium Variation Effect on Key Cellular Processes Using Morphological Profiling

Cells, Journal Year: 2025, Volume and Issue: 14(5), P. 336 - 336

Published: Feb. 25, 2025

Although every cell biologist knows the importance of selecting right growth conditions and it is well known that composition medium may vary depending on a product brand or lot affecting many cellular processes, still those effects are poorly systematized. We addressed this issue by comparing effect 12 fetal bovine sera (FBS) eight media from different brands morphological functional parameters five types: lung adenocarcinoma, neuroblastoma, glioblastoma, embryonic kidney, colorectal cancer cells. Using high-throughput imaging, we compared proliferation; performed profiling based imaging 561,519 cells; measured extracellular regulated kinases (ERK1/2) activity, mitochondria potential, lysosome accumulation; sensitivity to drugs, response EGF stimulation, ability differentiate. found changes in proliferation morphology were independent, associated with differences potential cell's Surprisingly, most drastic detected serum-free conditions, where choice affected survival EGF. Overall, our data be used improve reproducibility experiments involving cultures, 28 44 can explored through Shinyapp.

Language: Английский

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Improving the power of drug toxicity measurements by quantitative nuclei imaging

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: April 18, 2024

Imaging-based anticancer drug screens are becoming more prevalent due to development of automated fluorescent microscopes and imaging stations, as well rapid advancements in image processing software. Automated cell provides many benefits such their ability provide high-content data, modularity, dynamics recording the fact that is most direct way access viability proliferation. However, currently publicly available large-scale drugs screens, GDSC, CTRP NCI-60, data measured by assays based on colorimetric or luminometric measurements NADH ATP levels. Although datasets valuable it unclear how toxicity can be integrated with data. Here we explored relations between obtained XTT assay, two quantitative nuclei methods trypan blue dye exclusion assay using a set four cancer lines different morphologies 30 mechanisms action. We show imaging-based approaches high accuracy differences results highly depend mechanism Selecting AUC metrics over IC50 comparing where significantly reduced numbers noticeably improves consistency methods. Using segmentation protocols analyzed mitochondria activity than 11 thousand drug-treated cells showed produces unreliable for CDK4/6, Aurora A, VEGFR PARP inhibitors induced size growth increase individual activity. also several image-based analysis monitor number dynamics, dissect changes total from proliferation, identify chromatin remodeling drugs. Finally, web tool allows

Language: Английский

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Genome wide-scale CRISPR-Cas9 knockout screens identify a fitness score for optimized risk stratification in colorectal cancer

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: June 10, 2024

The molecular complexity of colorectal cancer poses a significant challenge to the clinical implementation accurate risk stratification. There is still an urgent need find better biomarkers enhance established stratification and guide risk-adapted treatment decisions.

Language: Английский

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Photocages Made to Order: Late-Stage Caging Protocol Enables Anti-Cancer Control with Near-Infrared Light

Published: July 24, 2024

Nature has perfected the reversible control over activity of molecules and biomolecules in human body. Photocages aim to mimic this space time using light as a trigger, field witnessed many excellent contributions that extend their use tissue-penetrating region. Yet little attention been paid developing simple caging strategies which are crucial translate photocages into widely accepted tool beyond chemical space. Here, we report robust user-friendly protocol enables installation amine, thiol phenol payloads single step under mild conditions bench-stable intermediates. The displays compatibility with payloads, manifested by hormones, neurotransmitters, tripeptide highly complex FDA-approved drugs, including antibiotics or anti-cancer agents. In proof-of-concept study, utilize strategy cage clinically used CDK4/6 inhibitor palbociclib tumor suppressing retinoblastoma protein breast cancer cells near-infrared (NIR) light. We anticipate normalizing access NIR-absorbing through will empower research across various scientific disciplines.

Language: Английский

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Elraglusib induces cytotoxicity via direct microtubule destabilization independently of GSK3 inhibition

Cancer Research Communications, Journal Year: 2024, Volume and Issue: 4(11), P. 3013 - 3024

Published: Oct. 29, 2024

Elraglusib was designed as a GSK3 inhibitor and is currently in clinical trials for several cancers. We show conclusively that the target of elraglusib leads to cytotoxicity MTs not GSK3. This has significant implications ongoing compound will help understanding off-target side effects, inform future trial design, facilitate development biomarkers predict response.

Language: Английский

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Elraglusib induces cytotoxicity via microtubule destabilisation independently of GSK3 inhibition

Published: July 8, 2024

A bstract Elraglusib (9-ING-41) is an ATP-competitive inhibitor of glycogen synthase kinase-3 (GSK3) with pre-clinical studies demonstrating broad activity against many tumour types. Promising early-phase clinical trial data led to FDA orphan drug status, and a randomized phase 2 study in combination cytotoxic chemotherapy pancreatic cancer has recently completed its recruitment. Similarly, single-agent responses adult T-cell leukaemia/lymphoma melanoma, treatment several other types have been encouraging. The elraglusib mechanism action unknown, but it unlikely act through GSK3 inhibition because cytotoxicity observed below the IC 50 for small molecule inhibitors do not produce effects, at least lymphoma cells. We show here that perturbs chromosomal alignment cause mitotic arrest multiple lines. This caused by direct microtubule depolymerisation, which prevents attachment kinetochores microtubules. At clinically relevant doses, these mitotically arrested cells eventually undergo slippage, leading gross chromosome missegregation, DNA damage apoptosis. These effects explain temporarily pausing cell cycle progression CDK4/6 palbociclib abolishes any drug-induced genotoxicity In summary, acts as potent destabilizer both vitro across types, resulting arrest, likely account pan-cancer activity, does rely upon they are replicated inhibitors.

Language: Английский

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P16INK4A drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination

iScience, Journal Year: 2024, Volume and Issue: 27(10), P. 110882 - 110882

Published: Sept. 3, 2024

P16

Language: Английский

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Targeting CDK4 and CDK6 in hormone-dependent cancers

Vitamins and hormones, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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