Donafenib activates the p53 signaling pathway in hepatocellular carcinoma, induces ferroptosis, and enhances cell apoptosis

Clinical and Experimental Medicine, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 3, 2025

Donafenib is an improved version of sorafenib in which deuterium substituted into the drug's chemical structure, enhancing its stability and antitumor activity. exhibits enhanced activity better tolerance than preclinical clinical studies. However, specific mechanism effect on hepatocellular carcinoma has not been reported. Iron deposition a cell death pattern caused by disturbances iron metabolism. Apoptosis form programmed death. They may interact with each other during This study mainly explores potential donafenib activating p53 signaling pathway, inducing deposition, apoptosis carcinoma. Hepa1-6 Huh7 cells were treated various concentrations donafenib. Scratch healing pore migration tests conducted. Analyze through flow cytometry TUNEL fluorescence labeling. RNA sequencing was conducted both untreated donafenib-treated cells. The key proteins involved ferroptosis (SLC7A11, GPX4) (caspase3, caspase8, Bax, Bcl-2, p53) then evaluated using immunoblotting immunohistochemical staining. Reactive oxygen species (ROS) levels cancer measured. treatment resulted dose-dependent decrease proliferation, migration, invasion capabilities There increase rates ROS accumulation, reduction tumor volume. underwent significant changes. activates induce ferroptosis, enhance apoptosis, suggesting as effective therapeutic agent for HCC.

Язык: Английский

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Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Янв. 15, 2025

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, chromatin remodeling, pancreatic tumors progression becoming increasingly recognized. Moreover, PDAC these aberrant mechanisms can also limit therapy efficacy. This study aimed to investigate the expression prognostic significance key complex encompassing methyltransferase-1 (DNMT1), histone methyltransferase G9a, scaffold protein UHRF1 PDAC. We evaluated therapeutic potential an innovative inhibitor targeting effectors. Methods Immunohistochemical analysis DNMT1, was conducted human tissue samples. Staining semi-quantitatively scored, overexpression defined moderate strong positivity. impact assessed by correlating patient survival. antitumoral effects dual DNMT1-G9a CM272 were tested cell lines, followed transcriptomic analyses identify underlying mechanisms. vivo efficacy xenograft syngeneic mouse models, both alone combination anti-PD1 immunotherapy. Results significantly overexpressed cells stroma compared normal tissues. Simultaneous three proteins associated reduced survival resected patients. exhibited potent antiproliferative activity inducing apoptosis altering metabolic cycle-related genes. enhanced chemotherapy sensitivity inhibited tumor growth without detectable toxicity. Combination further improved antitumor responses immune infiltration, particularly CD4 + CD8 T cells. Conclusions combined predictor CM272, this complex, shows promising apoptosis, reprogramming pathways, enhancing responses. immunotherapy offers novel, effective strategy for

Язык: Английский

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Identification of PRMT5 as a therapeutic target in cholangiocarcinoma

Gut, Год журнала: 2024, Номер 74(1), С. 116 - 127

Опубликована: Сен. 11, 2024

Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors limited. Therefore, new therapeutic strategies need be identified.

Язык: Английский

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Research update for ferroptosis and cholangiocarcinoma

Critical Reviews in Oncology/Hematology, Год журнала: 2024, Номер 198, С. 104356 - 104356

Опубликована: Апрель 18, 2024

Cholangiocarcinoma (CCA) is the second most common hepatobiliary malignancy after hepatocellular carcinoma. Due to poor treatment effect and high mortality rate of CCA, it great significance explore new therapeutic targets. Ferroptosis a type cell death caused by iron-dependent oxidative injury, which closely related occurrence development numerous diseases. Novel ideas for prevention diseases have been provided ferroptosis, has become focus research in recent years. This review introduces underlying mechanisms as well update ferroptosis CCA. The clinical value ferroptosis-related regulatory CCA will be elucidated.

Язык: Английский

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From metabolism to malignancy: the multifaceted role of PGC1α in cancer

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Май 7, 2024

PGC1α, a central player in mitochondrial biology, holds complex role the metabolic shifts seen cancer cells. While its dysregulation is common across major cancers, impact varies. In some cases, downregulation promotes aerobic glycolysis and progression, whereas others, overexpression escalates respiration aggression. PGC1α's interactions with distinct signaling pathways transcription factors further diversify roles, often tissue-specific manner. Understanding these multifaceted functions could unlock innovative therapeutic strategies. However, challenges exist managing adaptability of cells refining PGC1α-targeted approaches. This review aims to collate present current knowledge on expression patterns, regulators, binding partners, roles PGC1α diverse cancers. We examined elucidated dual nature as both potential tumor suppressor an oncogenic collaborator. cancers where tumor-suppressive, reinstating levels halt cell proliferation invasion, make more receptive chemotherapy. opposite true, halting upregulation can be beneficial it oxidative phosphorylation, allows adapt stress, aggressive phenotype. Thus, target effectively, understanding nuanced each subtype indispensable. pave way for significant strides field oncology.

Язык: Английский

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Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Май 14, 2025

Abstract Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation the serine synthesis pathway (SSP) can fuel tumor growth, cancers with this phenotype are often sensitive to SSP inhibitors. In parallel, dietary restriction glycine (SG) suppress some cancers, but determinants sensitivity approach poorly understood. This especially true acute myeloid leukemia (AML), where has been less explored. We report that a subset human AML cell lines primary samples completely dependent on external serine, known as auxotrophy. These leukemias consistently suppressed enzyme PSAT1, failed synthesize responded SG vivo , were rescued by restoring PSAT1. also found an SF3B1 K700E mutation showed additional dependence PHGDH, synergized venetoclax auxotrophic AML, MECOM rearrangement was strongly associated PSAT1 suppression findings define metabolically distinct subtype nominate it for targeting restriction.

Язык: Английский

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Inhibition of colorectal carcinogenesis by sunitinib malate: disruption of the IL-6/STAT3/c-MYC/TWIST/MMP2 autocrine signaling axis

Discover Oncology, Год журнала: 2025, Номер 16(1)

Опубликована: Май 23, 2025

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor with specificity for VEGFR, KIT, FLT3, and PDGFR, has demonstrated clinical efficacy as first- to third-line treatment refractory renal carcinoma. Our previous research indicated that sunitinib malate suppresses intestinal polyp proliferation by downregulating IL-6 mRNA expression, suggesting potential analogous mechanism in colorectal carcinoma inhibition. This study aimed elucidate the pharmacological effects molecular mechanisms of on using HCT116, RKO, HT29, SW480 cell lines vitro HCT116-derived xenografts nude mice vivo. We employed comprehensive array experimental techniques, including CCK-8/MTT assays viability, Transwell and/or wound healing migration, Western blot immunohistochemistry protein expression analysis. findings demonstrate significantly inhibits cancer migration vitro. Moreover, xenograft model, markedly suppressed tumor growth Notably, we observed significant downregulation c-MYC, TWIST, MMP2 both vivo following treatment. These results collectively suggest exerts its anti-colorectal effects, at least part, disrupting autocrine IL-6/STAT3/c-MYC/TWIST/MMP2 signaling axis.

Язык: Английский

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Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF-β inhibition

Journal of Experimental & Clinical Cancer Research, Год журнала: 2022, Номер 41(1)

Опубликована: Ноя. 28, 2022

Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor characterized by an intensive desmoplastic reaction due to the exaggerated presence of extracellular (ECM) matrix components. Liver fibroblasts close tumor, activated transforming growth factor (TGF)-β1 and expressing high levels α-smooth muscle actin (α-SMA), become cancer-associated (CAFs). CAFs are deputed produce secrete ECM components crosstalk with cancer cells favoring progression resistance therapy. Overexpression Notch signaling implicated in CCA development growth. The study aimed determine effectiveness inhibitor, Crenigacestat, on surrounding microenvironment iCCA.We investigated Crenigacestat's PDX model iCCA human primary culture isolated from patients iCCA.In silico analysis transcriptomic profiling tissues treated Crenigacestat highlighted "liver fibrosis" as one most modulated pathways. In model, treatment significantly (p < 0.001) reduced peritumoral liver fibrosis. Similar results were obtained hydrodynamic iCCA. Bioinformatic prediction upstream regulators related fibrosis revealed involvement TGF-β1 pathway master regulator gene showing robust connection between Consistently, drug 0.05) mRNA protein tumoral tissue. tissues, remarkably inhibited TGF-β expression α-SMA expression. Furthermore, synergistically increased Gemcitabine model. 31 patients, upregulated compared tissues. freshly iCCA, signaling, secretion, Smad-2 activation. Consequently, also inactivated reducing Finally, produced less 005) such fibronectin, collagen 1A1, 1A2.Notch inhibition reduces blocking canonical pathway.

Язык: Английский

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Capillary electrophoresis mass spectrometry-based untargeted metabolomics to approach disease diagnosis

TrAC Trends in Analytical Chemistry, Год журнала: 2023, Номер 162, С. 117049 - 117049

Опубликована: Апрель 2, 2023

Metabolites are the final products of metabolism and are, therefore, directly related to phenotype. They constitute metabolome an organism. The wide diversity physicochemical properties metabolites in terms molecular weight, concentration, polarity, volatility, solubility, pKa, charge makes their analysis a remarkable challenge. With over 220,000 recorded HMDB database, there is no single analytical technique capable analyzing all them. Therefore, multiple platforms required obtain comprehensive picture metabolome. Among these platforms, mass spectrometry (MS)-based techniques among most widely used. Capillary electrophoresis (CE) coupled MS has been employed analyze polar/ionic metabolites. Although this not used, it demonstrated unique capabilities for detection polar ionic that essential part usually detected by other techniques. This review highlights role CE-MS untargeted metabolomics, particularly comparison hydrophilic interaction chromatography (HILIC) separation mode. Additionally, we discuss metabolomics workflow including sample treatment analysis, data treatment, metabolite annotation. We notably present annotation tools developed explicitly CE-MS, as well some computational alternatives, in-house libraries relative migration times, effective mobility, MS/MS fragmentation, in-source CEU Mass Mediator online tool. Finally, mention future perspectives technique, such cell-CE ion mobility (IM)-MS. Overall, shows important studies published last five years approach human diseases.

Язык: Английский

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The present roles and future perspectives of Interleukin-6 in biliary tract cancer

Cytokine, Год журнала: 2023, Номер 169, С. 156271 - 156271

Опубликована: Июнь 16, 2023

Язык: Английский

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