BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer DOI Creative Commons
Jiahui Zhang, Xiaoli Liu, Peng Hou

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(7)

Published: July 31, 2024

Abstract PLK1 is currently at the forefront of mitotic research and has emerged as a potential target for small cell lung cancer (SCLC) therapy. However, factors influencing efficacy inhibitors remain unclear. Herein, BRCA1 was identified key factor affecting response SCLC cells to BI-2536. Targeting AURKA with alisertib, non-toxic concentration, reduced BI-2536-induced accumulation RAD51, leading DNA repair defects death in cells. In vivo experiments confirmed that combining BI-2536 alisertib impaired capacity significantly delayed tumor growth. Additionally, GSEA analysis loss- gain-of-function assays demonstrated MYC/MYCN signaling crucial determining sensitivity its combination alisertib. The study further revealed positive correlation between RAD51 expression / expression, negative IC 50 values Manipulating influenced restored MYC/MYCN-induced enhancement Our findings indicate MYC/MYCN-RAD51 axes govern This propose combined use novel therapeutic strategy treatment patients activation.

Language: Английский

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives DOI Creative Commons
Viola Previtali, Greta Bagnolini, Andrea Ciamarone

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 11488 - 11521

Published: July 2, 2024

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of growing number lethal targets led to significant expansion in the use lethality, far beyond poly(ADP-ribose) polymerase inhibitors used treat BRCA1/2-defective tumors. particular, molecular within DNA damage response have provided source that rapidly reached clinical trials. This Perspective focuses on most progress and their inhibitors, response, describing design associated therapeutic strategies. We will conclude by discussing current challenges new opportunities this promising field research, stimulate discussion medicinal chemistry community, allowing investigation reach its full potential.

Language: Английский

Citations

17
Novel 1,6-Naphthridine Compounds as SMARCA2 Inhibitors for Treating Non-small Cell Lung Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(3), P. 371 - 372

Published: Feb. 14, 2025

Provided herein are novel 1,6-naphthridine compounds as SMARCA2 inhibitors, pharmaceutical compositions, use of such in treating non-small cell lung cancer and processes for preparing compounds.

Language: Английский

Citations

1
1,6-Naphthridine Compounds as SMARCA2 Inhibitors for Treating Non-small Cell Lung Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Provided herein are novel 1,6-naphthridine compounds as SMARCA2 inhibitors, pharmaceutical compositions, use of such in treating non-small cell lung cancer and processes for preparing compounds.

Language: Английский

Citations

0
Antioxidants in cancer therapy mitigating lipid peroxidation without compromising treatment through nanotechnology DOI Creative Commons
Daniel Ejim Uti, Item Justin Atangwho, Esther Ugo Alum

et al.

Discover Nano, Journal Year: 2025, Volume and Issue: 20(1)

Published: April 24, 2025

Cancer treatments often exploit oxidative stress to selectively kill tumour cells by disrupting their lipid peroxidation membranes and inhibiting antioxidant enzymes. However, plays a dual role in cancer progression, acting as both promoter suppressor. Balancing through therapy remains challenge, excessive activity may compromise the efficacy of chemotherapy radiotherapy. This review explores antioxidants mitigating while maintaining treatment efficacy. It highlights recent advancements nanotechnology-based targeted delivery optimize therapeutic outcomes. A comprehensive literature was conducted using reputable databases, including PubMed, Scopus, Web Science, ScienceDirect. The search focused on publications from past five years (2020-2025), supplemented relevant studies earlier years. Keywords such "antioxidants," "lipid peroxidation," "nanotechnology therapy," "oxidative stress" were utilized. Relevant articles critically analysed, graphical illustrations created. Emerging evidence suggests that nanoparticles, liposomes, polymeric metal-organic frameworks, others, can effectively encapsulate control release minimizing systemic toxicity. Stimuli-responsive carriers with tumour-specific targeting mechanisms further enhance delivery. Studies indicate these strategies help preserve normal cells, mitigate stress-related damage, improve challenges bioavailability, stability, potential interactions standard therapies remain. Integrating nanotechnology antioxidant-based interventions presents promising approach for optimizing therapy. Future research should focus refining modulation strategies, assessing profiles during treatment, employing biomarkers determine optimal dosing. balanced use adverse effects.

Language: Английский

Citations

0
Alcohol Dehydrogenase 4‐Mediated Retinol Metabolism Inhibits Hepatocellular Carcinoma Progression Through Inhibiting the Wnt/β‐Catenin Pathway DOI Creative Commons

Jiaying Li,

Man Gao, Ya‐Nan Zhang

et al.

MedComm – Oncology, Journal Year: 2025, Volume and Issue: 4(2)

Published: April 24, 2025

ABSTRACT Hepatocellular carcinoma (HCC) ranks third in global cancer‐related mortality, with limited therapies for advanced stages. Retinol, the alcohol form of vitamin A, has long been associated liver diseases. Plasma retinol levels have inversely correlated risk and poor prognosis HCC. In this study, transcriptome data analysis identified metabolism as seventh KEGG‐dysregulated pathway cirrhosis tissue, ascending to top position HCC tissue compared normal tissue. Specifically, a consistent downregulation ADH4 (alcohol dehydrogenase 4), among human ADHs, was observed, which patients. vivo experiments demonstrated that silencing enhances fibrosis progression Mechanistically, elevated intracellular RA (retinoic acid), biologically active derivative retinol. RA‐activated retinoid receptors RARs/RXRs, leading inhibition downstream Wnt/β‐catenin thereby hindering progression. contrast, knockdown hepatocytes triggers apoptosis. Notably, additional results combined treatment cisplatin achieved synergistic antitumor effects mouse model. summary, our research elucidates ADH4‐mediated production suppresses growth, providing theoretical foundation treatment.

Language: Английский

Citations

0
SMARCB1 Deficiency as a Driver of the Hallmarks of Cancer in Rhabdoid Tumours: Novel Insights into Dysregulated Energy Metabolism, Emerging Targets, and Ongoing Clinical Trials DOI Creative Commons

Abdul L. Shakerdi,

Graham P. Pidgeon

Metabolites, Journal Year: 2025, Volume and Issue: 15(5), P. 304 - 304

Published: May 3, 2025

Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit highly malignant phenotype and poor prognosis. Methods: This review explores mechanisms underlying aberrations, role in driving hallmarks cancer, emerging therapeutic strategies for RTs. Ongoing clinical trials listed on ClinicalTrials were reviewed to evaluate translational potential targeted therapies SMARCB1-deficient rhabdoid tumours. Results: Loss drives multiple cancer disrupting key regulatory pathways. It promotes unchecked cell proliferation through alterations p16INK4a Myc signalling. possess immune-evading capabilities via PD-L1 overexpression immune checkpoint activation. deficiency also alters cellular energetics. The nucleotide biosynthesis pathway has been demonstrated be upregulated RT organoids, as shown increased levels metabolites. Enzymes mevalonate such HMG-CoA reductase kinase dysregulated. Targeting glutathione metabolism with eprenetapopt may induce oxidative stress apoptosis. Widespread epigenetic including EZH2 activity, being inhibitors tazemetostat. Conclusions: is central driver RTs, enabling proliferation, evasion, metabolic reprogramming, dysregulation. Future horizons treatment include immunotherapies, modifiers, gene therapies. synergy optimal timing therapy conventional requires further characterisation translation.

Language: Английский

Citations

0
Identification of Anticancer Enzymes and Biomarkers for Hepatocellular Carcinoma through Constraint-Based Modeling DOI Creative Commons
Feng‐Sheng Wang, Hao-Xiang Zhang

Molecules, Journal Year: 2024, Volume and Issue: 29(11), P. 2594 - 2594

Published: May 31, 2024

Hepatocellular carcinoma (HCC) results in the abnormal regulation of cellular metabolic pathways. Constraint-based modeling approaches can be utilized to dissect reprogramming, enabling identification biomarkers and anticancer targets for diagnosis treatment. In this study, two genome-scale models (GSMMs) were reconstructed by employing RNA sequencing expression patterns hepatocellular their healthy counterparts. An target discovery (ACTD) framework was integrated with identify HCC The ACTD encompassed four fuzzy objectives assess both suppression cancer cell growth minimization side effects during composition a nutrient may significantly affect identification. Within framework, ten distinct media uptake identifying potential enzymes. findings revealed successful enzymes within cholesterol biosynthetic pathway using cholesterol-free culture medium. Conversely, not identified when included component. Moreover, PGS1 CRL1 detected all media. Additionally, comprises dual-group representations combinations, pairing single-target enzyme an additional reaction. across ten-nutrient Furthermore, encompasses two-group combinations involving Computational analysis unveiled that viability dual-target exceeded respective Consequently, integrating while adjusting exchange reaction could efficiently mitigate proliferation rates ATP production treated cells. Nevertheless, most led lower contrast differential metabolites between cells counterparts assessed via parsimonious flux variability GSMMs pinpoint biomarkers. variabilities fluxes metabolite flow classified into seven categories. Accordingly, secretions thirteen uptakes (including eight essential amino acids conditionally acids) as study indicated exhibit higher compared

Language: Английский

Citations

1
BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer DOI Creative Commons
Jiahui Zhang, Xiaoli Liu, Peng Hou

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(7)

Published: July 31, 2024

Abstract PLK1 is currently at the forefront of mitotic research and has emerged as a potential target for small cell lung cancer (SCLC) therapy. However, factors influencing efficacy inhibitors remain unclear. Herein, BRCA1 was identified key factor affecting response SCLC cells to BI-2536. Targeting AURKA with alisertib, non-toxic concentration, reduced BI-2536-induced accumulation RAD51, leading DNA repair defects death in cells. In vivo experiments confirmed that combining BI-2536 alisertib impaired capacity significantly delayed tumor growth. Additionally, GSEA analysis loss- gain-of-function assays demonstrated MYC/MYCN signaling crucial determining sensitivity its combination alisertib. The study further revealed positive correlation between RAD51 expression / expression, negative IC 50 values Manipulating influenced restored MYC/MYCN-induced enhancement Our findings indicate MYC/MYCN-RAD51 axes govern This propose combined use novel therapeutic strategy treatment patients activation.

Language: Английский

Citations

1