Synthesis of 1,10‐phenanthroline‐2,9‐bistriazoles: Evaluation as G‐quadruplex binders and anti‐tumor activity DOI
Joana Figueiredo, Israel Carreira‐Barral, Pedro Lourenço

et al.

ChemMedChem, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 2, 2024

Abstract Novel 1,10‐phenanthroline‐2,9‐bistriazoles derivatives have been synthesized by copper‐catalyzed azide/alkyne cycloaddition reactions and assessed for their ability to bind stabilize G‐quadruplex (G4) structures. Ten novel compounds were evaluated using Förster resonance energy transfer (FRET) melting, circular dichroism (CD), fluorescence spectroscopy on several G4 sequences. Biophysical characterization led the identification of 4 a , b 5 as good ligands KRAS The impact cell viability all was also assessed, revealing weak effects. However, compound 2 exhibited cytotoxicity activity A549 H1299 cancer cells low towards MRC‐5 non‐malignant not connected with its G4‐binding ability. Flow cytometry showed that induced decrease in S G2/M phases H1299; thus, more studies should be performed explore proteins involved cycle regulation.

Language: Английский

CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence DOI Creative Commons
Lisa Crozier, Reece Foy, Rozita Adib

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(22), P. 4062 - 4077.e5

Published: Nov. 1, 2023

Abnormal increases in cell size are associated with senescence and cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the remain unknown. We address this question using CDK4/6 inhibitors, arrest G0/G1 licensed treat advanced HR+/HER2- breast cancer. demonstrate that CDK4/6-inhibited overgrow during G0/G1, causing p38/p53/p21-dependent withdrawal. Cell withdrawal is triggered biphasic p21 induction. first wave caused osmotic stress, leading p38- size-dependent accumulation of p21. inhibitor washout results some entering S-phase. Overgrown experience replication resulting a second promotes G2 or subsequent G1. propose levels integrate signals overgrowth-triggered stresses determine fate. This model explains how hypertrophy can drive why inhibitors have long-lasting effects patients.

Language: Английский

Citations

42
Genome homeostasis defects drive enlarged cells into senescence DOI Creative Commons
Sandhya Manohar, Marianna E. Estrada, Federico Uliana

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(22), P. 4032 - 4046.e6

Published: Nov. 1, 2023

Cellular senescence refers to an irreversible state of cell-cycle arrest and plays important roles in aging cancer biology. Because is associated with increased cell size, we used reversible arrests combined growth rate modulation study how excessive affects proliferation. We find that enlarged cells upregulate p21, which limits progression. Cells re-enter the cycle encounter replication stress well tolerated physiologically sized but causes severe DNA damage cells, ultimately resulting mitotic failure permanent withdrawal. demonstrate fail recruit 53BP1 other non-homologous end joining (NHEJ) machinery sites robustly initiate damage-dependent p53 signaling, rendering them highly sensitive genotoxic stress. propose impaired response primes for persistent replication-acquired damage, leading division exit.

Language: Английский

Citations

37
Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition DOI Creative Commons
Gemma A. Wilson, Karla Vuina, Georgina P. Sava

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(22), P. 4078 - 4092.e6

Published: Nov. 1, 2023

Tumor growth is driven by continued cellular and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs global gene expression makes it therefore an attractive target for cancer therapies. However, what cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear.Here, we address this question. We show that CDK7i, samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified active mTOR (mammalian of rapamycin) promotes samuraciclib-induced senescence. decreases samuraciclib sensitivity, increased mTOR-dependent correlates with sensitivity lines. Reverting growth-promoting mutation PIK3CA wild type CDK7i. Our work establishes enhanced alone CDK7i providing explanation why some cancers are more CDK than normally growing cells.

Language: Английский

Citations

31
Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer DOI
Xianbing Zhu, Zheng Fu, Kendall Dutchak

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(8), P. 1333 - 1351

Published: Jan. 26, 2024

Abstract Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non–small cell lung (NSCLC). However, the clinical efficacy of CDK4/6 is limited due to frequent drug resistance their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred inhibitor palbociclib in NSCLC cells. Inhibition BRD4, either by RNA interference or small-molecule inhibitors, synergized with induce senescence cells tumors, combination prolonged survival mouse model. Mechanistically, BRD4-inhibition enhanced cell-cycle arrest reactive oxygen species (ROS) accumulation, both which necessary induction; this turn elevated GPX4, peroxidase suppresses ROS-triggered ferroptosis. Consequently, GPX4 selectively induced ferroptotic death senescent cells, resulting tumor regression. Cotargeting BRD4 also promoted ferroptosis vulnerability pancreatic Together, these findings reveal therapeutic vulnerabilities effective combinations enhance utility inhibitors. Significance: The induces primed activation targeting providing an strategy treating cancer.

Language: Английский

Citations

15
Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment DOI Creative Commons
Antonino Glaviano, Seth A. Wander, Richard D. Baird

et al.

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 76, P. 101103 - 101103

Published: June 25, 2024

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent 6 (CDK6) are key molecules in the G1-to-S phase transition crucial for onset, survival, progression breast (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation tumor suppressor Rb thus restrain susceptible BC cells G1 phase. Three CDK4/6i approved first-line treatment patients with advanced/metastatic hormone receptor-positive (HR

Language: Английский

Citations

14
Natural polyphenols: A protective approach to reduce colorectal cancer DOI Creative Commons
Joel Okpoghono, Endurance Fegor Isoje, Ufuoma Augustina Igbuku

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(11), P. e32390 - e32390

Published: June 1, 2024

A form of cancer that affects the rectum or colon (large intestine) is called colorectal (CRC). The main risk factors for CRC include dietary, lifestyle, and environmental variables. Currently natural polyphenols have demonstrated impressive anticarcinogenic capabilities.

Language: Английский

Citations

10
The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays DOI Creative Commons
Reece Foy,

Kah Xin Lew,

Adrian T. Saurin

et al.

npj Breast Cancer, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 4, 2024

CDK4/6 inhibitors are effective at treating advanced HR+ /HER2- breast cancer, however biomarkers that can predict response urgently needed. We demonstrate here previous large-scale screens designed to identify which tumour types or genotypes most sensitive have misrepresented the responsive cell lines because of a reliance on metabolic proliferation assays. CDK4/6-inhibited cells arrest in G1 but continue grow size, thereby producing more mitochondria. show this growth obscures using ATP-based assays not if DNA-based used instead. Furthermore, lymphoma lines, previously identified as sensitive, simply appear respond best they fail overgrow during arrest. Similarly, inhibitor abemaciclib appears inhibit better than palbociclib it also restricts cellular overgrowth through off-target effects. DepMap analysis screening data reliable assay types, demonstrates palbociclib-sensitive Cyclin D1, CDK4 and CDK6 knockout/knockdown, whereas palbociclib-resistant E1, CDK2 SKP2 knockout/knockdown. Potential increased expression CCND1 RB1, reduced CCNE1 CDKN2A. Probing with similar from fails reveal these associations. Together, why inhibitors, any other anti-cancer drugs cycle permit continued growth, must now be re-screened against wide-range an appropriate assay. This would help inform clinical trials much needed response.

Language: Английский

Citations

9
Genome dilution by cell growth drives starvation-like proteome remodeling in mammalian and yeast cells DOI
Michael C. Lanz, Shuyuan Zhang, Matthew P. Swaffer

et al.

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

Language: Английский

Citations

9
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype DOI Creative Commons

J. P. W. Joung,

Y.‐A. Heo,

Yeonju Kim

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 17, 2025

Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although enlargement is a prominent morphological feature of cellular senescence, its functional implications unknown; moreover, how senescent cells maintain their state less understood. Here we show that an extensive remodeling actin cytoskeleton necessary for establishing senescence-associated pro-inflammatory secretory phenotype (SASP). This attributed to balancing act between the SASP regulator GATA4 mechanosensor YAP on expression Rho family GTPase RHOU. Genetic or pharmacological interventions reduce attenuate minimal effect senescence growth arrest. Mechanistically, couples nuclear localization NF-κB via Linker Nucleoskeleton Cytoskeleton (LINC) complex. RhoU protein accumulates mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU correlates during human Thus, our study highlights unexpected instructive role modulating reveals mechanical branch regulatory network. Senescent accumulate aging exhibit enlargement, function which has been unclear decades. Here, authors identify antagonistic genetic circuit hypertrophy reveal SASP.

Language: Английский

Citations

1
Eukaryotic cell size regulation and its implications for cellular function and dysfunction DOI
Yagya Chadha, Arohi Khurana, Kurt M. Schmoller

et al.

Physiological Reviews, Journal Year: 2024, Volume and Issue: 104(4), P. 1679 - 1717

Published: June 20, 2024

Depending on cell type, environmental inputs, and disease, the cells in human body can have widely different sizes. In recent years, it has become clear that size is a major regulator of function. However, we are only beginning to understand how optimization function determines given cell’s optimal size. Here, review currently known control strategies eukaryotic intricate link intracellular biomolecular scaling, organelle homeostasis, cycle progression. We detail size-dependent regulation early development impact differentiation. Given importance for normal cellular physiology, must account changing conditions. describe sense stimuli, such as nutrient availability, accordingly adapt their by regulating growth Moreover, discuss correlation pathological states with misregulation long time this was considered downstream consequence dysfunction. newer studies reveal reversed causality, misregulated leading pathophysiological phenotypes senescence aging. summary, highlight important roles dysfunction, which could implications both diagnostics treatment clinic.

Language: Английский

Citations

5