Combination immune checkpoint and targeted protein kinase inhibitors for the treatment of renal cell carcinomas

Pharmacological Research, Journal Year: 2024, Volume and Issue: 203, P. 107181 - 107181

Published: April 12, 2024

Kidney cancers comprise about 3% of all new malignancies in the United States. Renal cell carcinomas (RCCs) are most common type renal malignancy making up 85% kidney cancer cases. Signs and symptoms can result from local tumor growth, paraneoplastic syndromes, or distant metastases. The classic triad presentation with flank pain, hematuria, a palpable abdominal mass occurs fewer than 10% patients. Most diagnoses incidental imaging findings (ultrasonography CT imaging) performed for another reason. Localized disease is treated by partial nephrectomy, total ablation (tumor destruction heat cold). When tumors have metastasized, systemic therapy protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, stem factor growth receptors (VEGFR, PDGFR, FGFR, MET, Kit) were prescribed after 2005. monoclonal antibody immune checkpoint inhibitor nivolumab (targeting programed death protein 1, PD1) was approved treatment RCCs 2015. It usually used now combination ipilimumab CTLA-4) cabozantinib (a multikinase blocker). Other therapies include pembrolizumab axitinib VEGFR PDGFR blocker) lenvatinib inhibitor). Since KEYNOTE-426 clinical trial, use inhibitors standard care patients metastatic monotherapies only those individuals who cannot receive tolerate inhibitors.

Language: Английский

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Targeting ferroptosis: a new therapeutic opportunity for kidney diseases

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 3, 2024

Ferroptosis is a form of non-apoptotic regulated cell death (RCD) that depends on iron and characterized by the accumulation lipid peroxides to lethal levels. involves multiple pathways including redox balance, regulation, mitochondrial function, amino acid, lipid, glycometabolism. Furthermore, various disease-related signaling also play role in regulating process oxidation. In recent years, with emergence concept ferroptosis in-depth study its mechanisms, closely associated biological conditions related kidney diseases, organ development, aging, immunity, cancer. This article reviews development ferroptosis, mechanisms (including GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, GCH1-BH4, MBOAT1/2 pathways), latest research progress involvement diseases. It summarizes diseases within frameworks metabolism, reactive oxygen biology, biology. The introduces key regulatory factors as well important concepts major open questions natural compounds. hoped future research, further breakthroughs can be made understanding regulation mechanism utilizing promote treatments for such acute injury(AKI), chronic disease (CKD), diabetic nephropathy(DN), renal carcinoma. paves way new approach prevent, treat clinical

Language: Английский

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MiR-501-3p/SPC24 axis affects cell proliferation, migration, invasion, apoptosis, and prognosis in renal cell carcinoma

Brazilian Journal of Medical and Biological Research, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

It has been confirmed that the expression of miR-501-3p is closely related to behavior several cancers. This study aimed elucidate effects miR-501-3p/SPC24 axis on renal cancer cells and identify its prognostic value in cancer. First, cell carcinoma (RCC) line was detected using real-time quantitative polymerase chain reaction (RT-qPCR). Second, function identification experiments were performed, including CCK-8, scratch, transwell invasion, flow cytometry assays. Several databases applied explore possible mechanism tumor suppressor effect RCC. To predicting patient overall survival (OS), GEPIA (http://gepia.cancer-pku.cn/index.html) used. Finally, western blot performed detect level SPC24 predicted by bioinformatics analysis. Dual-Luciferase Reporter Assay used verify if a target mir-501-3p. MiR-501-3p found be down-regulated tissues play role suppressing proliferation, viability, migration, while promoting apoptosis. We also high levels associated with shorter OS time patients diagnosed carcinoma. In addition, results TCGA data analysis showed may achieved targeting SPC24. The MiR-501-3p/SPC24 affects apoptosis, prognosis

Language: Английский

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Design, Synthesis, and In Silico Insights of new 4‐Piperazinylquinolines as Antiproliferative Agents against NCI Renal Cancer Cell Lines

ChemistryOpen, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Abstract In the search for new anticancer compounds, quinoline and piperazine moieties represent most promising pharmacophoric fragments development of more effective drugs. A particularly interesting approach in medicinal chemistry is molecular hybridization, where different known components are integrated into a single chemical entity, resulting hybrid molecules with enhanced biological activity. this study, we have developed series 4‐(4‐benzoylpiperazin‐1‐yl)‐6‐nitroquinoline‐3‐carbonitrile compounds ( 8 – l ), potential effect, by combining quinoline, piperazinyl benzoylamino moieties. The rationalized ) were first evaluated silico to assess ADMET drug‐likeness profiles, synthesized using appropriate synthetic strategies then tested vitro under National Cancer Institute DTP‐NCI60 program. entire exhibited potent activity against renal cell carcinoma (RCC) line UO‐31, c g effectively inhibiting cancer growth without excessive cytotoxic effects (growth percentages −7 −19, respectively). induced fit docking (IFD) dynamics (MD) studies provided further insights putative mechanisms action both which predicted strongly bind key oncogenic proteins involved RCC progression. results herein presented provide solid foundation small heterocyclic

Language: Английский

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2‐Undecanone induces ferroptosis via the STAT3/GPX4 pathway to enhance sensitivity of renal cell carcinoma to sunitinib

BioFactors, Journal Year: 2025, Volume and Issue: 51(2)

Published: March 1, 2025

Abstract The development of resistance significantly reduces the efficacy targeted therapies, such as sunitinib, in renal cell carcinoma (RCC) patients, emphasizing need for novel therapeutic agents. Natural products, known their diverse chemical structures and mechanisms action, offer promising anti‐tumor potential with favorable safety profiles lower toxicity compared to synthetic drugs. 2‐Undecanone, a natural compound extracted from Houttuynia cordata Thunb., has demonstrated effects, but its specific role RCC treatment remains unclear. In this study, we integrated network pharmacology vitro experiments explore underlying 2‐Undecanone's effects on RCC. Our results reveal that 2‐Undecanone effectively inhibits viability, proliferation, migration. Mechanistically, discovered induces ferroptosis cells by promoting reactive oxygen species (ROS) generation, intracellular Fe 2+ accumulation, glutathione (GSH) production, lipid peroxidation, modulation STAT3/GPX4 signaling pathway. Furthermore, lowers IC50 value sunitinib cells, enhancing sensitivity therapy. Additionally, potentiates sunitinib‐induced ferroptosis. summary, our research reveals enhances through targeting pathway, providing new insights into strategies

Language: Английский

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AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments

Heliyon, Journal Year: 2024, Volume and Issue: 10(14), P. e34834 - e34834

Published: July 1, 2024

Clear Cell Renal Carcinoma (ccRCC), the most prevalent form of renal cell carcinoma (RCC), poses a significant threat to human health due its rising morbidity and mortality rates. Sunitinib, pivotal targeted drug for treatment ccRCC, presents challenge high susceptibility ccRCC resistance. HSP90 inhibitor AUY922 has demonstrated anti-tumor activity in range cancer types. However, efficacy combination with sunitinib not been evaluated. In this study, we employed bioinformatics, network pharmacology, vitro assays verify that inhibits viability, proliferation, migration lines 786-O ACHN, IC50s 91.86 μM 115.5 ACHN. The effect enhancing inhibitory on was further confirmed. CCK-8 assay IC50 reduced from 15.10 11.91 17.65 13.66 after combined application AUY922. EdU wound healing indicated augmented impact proliferation cells. Western blot RT-PCR analyses increased sensitivity cells by targeting HIF-1α/VEGFA/VEGFR pathway. Our study represents first investigation into role mechanism sunitinib. conclusion, findings indicate potential enhance therapeutic overcome resistance ccRCC.

Language: Английский

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Natural polysaccharides as promising reno-protective agents for the treatment of various kidney injury

Pharmacological Research, Journal Year: 2024, Volume and Issue: 207, P. 107301 - 107301

Published: July 14, 2024

Renal injury, a prevalent clinical outcome with multifactorial etiology, imposes substantial burden on society. Currently, there remains lack of effective management and treatments. Extensive research has emphasized the diverse biological effects natural polysaccharides, which exhibit promising potential for mitigating renal damage. This review commences pathogenesis four common diseases shared mechanisms underlying injury. The renoprotective roles polysaccharides in vivo vitro are summarized following five aspects: anti-oxidative stress effects, anti-apoptotic anti-inflammatory anti-fibrotic gut modulatory effects. Furthermore, we explore structure-activity relationship bioavailability relation to as well investigate their utility biomaterials alleviating experiments applied patients chronic kidney disease also reviewed. Broadly, this provides comprehensive perspective direction context primary aim serve reference development pharmaceuticals prebiotics treatment diseases.

Language: Английский

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Novel thiazole/ethyl thiazole carboxylate-acetamide derivatives and their cytotoxic effect evaluation

Kocatepe Veterinary Journal, Journal Year: 2024, Volume and Issue: unknown

Published: May 28, 2024

In this study, the main goal is to determine anticancer compound(s) that can be used against A549 non-small lung epithelial carcinoma, Caco-2 colon and SHSY-5Y neuroblastoma cells with high selectivity. For purpose, our study group synthesized two similar acetamide series: four compounds (3a–3d), including thiazole, (3e–3h), ethyl (4-methyl-thiazol-5-yl)carboxylate. The structural analyses of eight were identified by HRMS, 1H-NMR, 13C-NMR. After approving purity, their profiles evaluated above cancer cells, cytotoxicity effect was also tested NIH/3T3 fibroblast cells. Meanwhile, ADME DFT calculations indicated have good chemical stability. Among targeted compounds, compound 3g exhibits greater systems, stability important because it represents energy balance within a molecule. results showed significant impact on higher selectivity than other combination ester groups thiazole thiazoline (compound 3g) found significantly more effective doxorubicin highly selective healthy Besides that, triazole (3d 3h) decreased antiproliferative activity in three while increasing This suggests future perspectives studies regarding treatments its related diseases 2-acetamido-4-methylthiazole-5-carboxylate are encouraging.

Language: Английский

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Response Gene to Complement 32 is Associated with Poor Patient Survival and an Inflamed Tumor-Immune Microenvironment in Clear Cell Renal Cell Carcinoma

Published: Jan. 1, 2024

Language: Английский

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In Silico Screening of 1,3,4-Thiadiazole Derivatives as Inhibitors of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(10), P. 11220 - 11235

Published: Oct. 6, 2024

Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed many human making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead compounds azole moiety exhibiting VEGFR-2 inhibitory effects. A ligand-based pharmacophore model was constructed using X-ray crystallographic structure complexed tivozanib (PDB ID: 4ASE) screen ZINC15 database. Following virtual screening, six demonstrated promising docking scores drug-likeness comparable tivozanib. These hits underwent detailed pharmacokinetic analysis assess their absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Furthermore, Density Functional Theory (DFT) employed investigate molecular orbital properties top from docking. Molecular dynamics (MD) simulations were conducted evaluate conformational stability complexes over 100 ns run. Results indicated that (ZINC8914312, ZINC8739578, ZINC8927502, ZINC17138581) exhibited most requirements inhibiting suppressing angiogenesis cancer therapy. integrated approach, combining modeling, docking, ADMET studies, DFT analysis, MD simulations, provides valuable insights into identification agents targeting VEGFR-2.

Language: Английский

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