Tumor hypoxia evidences the differential regulation of Mdm2-p53 axis by PTEN in tumor derived vs. normal endothelial cells DOI Creative Commons
Kinga Wilkus, Klaudia Brodaczewska,

Claudine Kieda

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Dec. 30, 2024

Hypoxia, a condition of oxygen tension lower than physiological level, plays crucial role in shaping the tumor microenvironment and modulates distinct cell populations activity. The suppressor PTEN regulates angiogenesis, process involving endothelial cells (ECs). Pathological tumors, it is for growth. As p53, key regulator ECs growth/angiogenic activity, appears to be target enabling repair pathologic angiogenesis. This study aims compare derived from breast cancer (HBCa.MEC) site with those healthy tissue (HBH.MEC). Hypoxia increased angiogenic activity HBCa.MEC vs. HBH.MEC, as showed an increased. Ability form vessels vitro. Low pO2 reduced total level Mdm2 protein expression leading elevated levels their phosphorylation-dependent HBCa.MEC, what was not changed ECs. Additionally, when Mdm2-p53 interaction inhibited, hypoxic reaching normoxic response. In conclusion, PTEN-mediated control pathological angiogenesis occurs by modulation Mdm2/p53 context microenvironment. emerges potential therapeutic normalizing treatment strategies.

Language: Английский

IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response DOI Creative Commons

Mingyue Yao,

Wenzhong Yan, Wang Yf

et al.

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: Feb. 15, 2025

Despite initial success with FLT3 inhibitors (FLT3is), outcomes for FLT3-ITD acute myeloid leukemia (AML) patients remain unsatisfactory, underscoring the need more effective treatment options. Epigenetic modifications, such as histone acetylation, contribute to AML's onset and persistence, advocating potential epigenetic therapies. However, poor specificity of pan-histone deacetylase (HDACis) leads undesirable adverse effects, prompting isoform-specific HDACis. This study aims explore antileukemic activities mechanisms IHCH9033, a novel class I HDACi, alone or combined FLT3i in AML. The viability AML cell lines primary cells treated HDACis combination was detected by MTT CCK8 assay. Flow cytometry utilized examine apoptosis, cycle progression ROS production. RNA sequencing analysis, RT-qPCR, western blotting, co-immunoprecipitation assays were employed elucidate molecule mechanisms. vivo anti-leukemia efficacy tested xenografted mice models derived from patients. Here, we identified selective which exhibited an increased antitumor effect through effectively eliminating burden overcoming resistance FLT3i. Mechanically, IHCH9033 selectively inhibited DNA repair cells, leading accumulation damage that eventually resulted arrest apoptosis. Additionally, induced HSP90 ubiquitination, proteasomal degradation FLT3, thereby inhibiting downstream signaling. Notably, maintained its potency both FLT3i-resistant primary-resistant patient samples, exerted strong synergy quizartinib, tumor regression FLT3-ITD/TKD xenografts. In patient-derived xenografts, combination, led nearly complete eradication burden, without significant effects. Our shows HDACi desirable pharmacological profile, is promising drug candidate AML, suggests strategy combining FLT3is clinical trials increase overcome resistance, thus potentially providing curative option.

Language: Английский

Citations

1
Targeting the DNA damage response in cancer DOI Creative Commons

Guffanti Federica,

Chiappa Michela,

Giovanna Damia

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(11)

Published: Oct. 31, 2024

DNA damage response (DDR) pathway is the coordinated cellular network dealing with identification, signaling, and repair of damage. It tightly regulates cell cycle progression promotes to minimize daughter cells. Key proteins involved in DDR are frequently mutated/inactivated human cancers promote genomic instability, a recognized hallmark cancer. Besides being an intrinsic property tumors, also represents unique therapeutic opportunity. Indeed, inhibition expected delay repair, causing persistent unrepaired breaks, interfere progression, sensitize cancer cells several DNA-damaging agents, such as radiotherapy chemotherapy. In addition, defects have been shown render these more dependent on remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over past two decades has led synthesis testing hundreds small inhibitors against key proteins, some antitumor activity cancers. parallel, search for synthetic lethality interaction broadening use inhibitors. this review, we discuss state-of-art ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 Polθ inhibitors, highlighting results obtained ongoing clinical trials both monotherapy combination chemotherapy radiotherapy.

Language: Английский

Citations

4
Cruciferae-based oral selenium delivery system reprograms antitumor response and enhances the anti-tumor potency of natural killer cells DOI

Shuoshan Li,

Guizhen Li, Kexin Guo

et al.

Nano Today, Journal Year: 2025, Volume and Issue: 62, P. 102713 - 102713

Published: March 17, 2025

Language: Английский

Citations

0
Protease-Hydrolysis-Driven Approach towards the Quantification of Cellular mRNA after Drug Treatment in Protein Nanopores DOI

Ling Zheng,

Jizhen Lin,

W. W. Tian

et al.

Analytica Chimica Acta, Journal Year: 2025, Volume and Issue: unknown, P. 343955 - 343955

Published: March 1, 2025

Language: Английский

Citations

0
Key molecular DNA damage responses of human cells to radiation DOI Creative Commons
Chengchen Zhang, Ji‐Bin Liu, Jun Wu

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 10, 2024

Our understanding of the DNA damage responses human cells to radiation has increased remarkably over recent years although some notable signaling events remain be discovered. Here we provide a brief account key molecular reflect current underlying mechanisms involved.

Language: Английский

Citations

1
Mechanistic insights into acetamiprid-induced genotoxicity on the myocardium and potential ameliorative role of resveratrol DOI
Rehab E. Abdelrahman, Mohamed Hassan, Marwa Ibrahim

et al.

Environmental Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 110, P. 104526 - 104526

Published: Aug. 5, 2024

Language: Английский

Citations

1
Molecular Signaling and Clinical Implications in the Human Aging-cancer Cycle DOI
Abdol-Hossein Rezaeian, Wenyi Wei

Seminars in Cancer Biology, Journal Year: 2024, Volume and Issue: 106-107, P. 28 - 42

Published: Aug. 26, 2024

Language: Английский

Citations

0
Synergistic Combination of Quercetin and Mafosfamide in Treatment of Bladder Cancer Cells DOI Creative Commons
Carmela Spagnuolo,

Francesco Mautone,

Anna Maria Iole Meola

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(21), P. 5176 - 5176

Published: Oct. 31, 2024

Bladder cancer, which has a rising incidence, is the 10th most common cancer. The transitional cell carcinoma histotype aggressive and often current therapies are ineffective. We investigated anti-proliferative effect of quercetin, natural flavonoid, in combination with alkylating agent mafosfamide (MFA) on two human bladder cancer lines, namely RT112 J82, representing progression from low-grade to high-grade tumors, respectively. In both types, combined treatment led synergic reduction viability confirmed by index less than one, though different biological responses were noted. J82 cells, MFA alone and, lesser extent, quercetin caused cycle arrest G2/M phase, but only triggered apoptotic death. contrast, induced autophagy, evidenced autophagosome formation increase LC-3 lipidation. Interestingly, synergistic was observed when cells pre-treated for 24 h before adding not reverse order. This suggests that may help overcome resistance apoptosis. Although further studies needed, investigating effects could elucidate mechanisms drug treatment.

Language: Английский

Citations

0
AZD1390, an Ataxia Telangiectasia Mutated Inhibitor, Enhances Cisplatin Mediated Apoptosis in Breast Cancer Cells DOI
Deniz ÖZDEMİR, Can Ali Ağca

Experimental Cell Research, Journal Year: 2024, Volume and Issue: unknown, P. 114382 - 114382

Published: Dec. 1, 2024

Language: Английский

Citations

0
Tumor hypoxia evidences the differential regulation of Mdm2-p53 axis by PTEN in tumor derived vs. normal endothelial cells DOI Creative Commons
Kinga Wilkus, Klaudia Brodaczewska,

Claudine Kieda

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Dec. 30, 2024

Hypoxia, a condition of oxygen tension lower than physiological level, plays crucial role in shaping the tumor microenvironment and modulates distinct cell populations activity. The suppressor PTEN regulates angiogenesis, process involving endothelial cells (ECs). Pathological tumors, it is for growth. As p53, key regulator ECs growth/angiogenic activity, appears to be target enabling repair pathologic angiogenesis. This study aims compare derived from breast cancer (HBCa.MEC) site with those healthy tissue (HBH.MEC). Hypoxia increased angiogenic activity HBCa.MEC vs. HBH.MEC, as showed an increased. Ability form vessels vitro. Low pO2 reduced total level Mdm2 protein expression leading elevated levels their phosphorylation-dependent HBCa.MEC, what was not changed ECs. Additionally, when Mdm2-p53 interaction inhibited, hypoxic reaching normoxic response. In conclusion, PTEN-mediated control pathological angiogenesis occurs by modulation Mdm2/p53 context microenvironment. emerges potential therapeutic normalizing treatment strategies.

Language: Английский

Citations

0