Fitoterapia, Journal Year: 2022, Volume and Issue: 162, P. 105278 - 105278
Published: Aug. 12, 2022
Language: Английский
Journal of Hepatocellular Carcinoma, Journal Year: 2024, Volume and Issue: Volume 11, P. 113 - 129
Published: Jan. 1, 2024
Abstract: Hepatocellular carcinoma is the prevailing malignant neoplasm affecting liver, often diagnosed at an advanced stage and associated with unfavorable overall prognosis. Sorafenib Lenvatinib have emerged as first-line therapeutic drugs for hepatocellular carcinoma, improving prognosis these patients. Nevertheless, issue of tyrosine kinase inhibitor (TKI) resistance poses a substantial obstacle in management carcinoma. The pathogenesis advancement exhibit close association metabolic reprogramming, yet attention given to lipid metabolism dysregulation development remains relatively restricted. This review summarizes potential significance research progress dysfunction Targeting holds promising effective strategy overcome drug future. Keywords: metabolism, sorafenib, lenvatinib, targeted
Language: Английский
Citations
6
Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(8), P. 104069 - 104069
Published: Aug. 1, 2024
Language: Английский
Citations
5
Inflammopharmacology, Journal Year: 2024, Volume and Issue: 32(5), P. 3461 - 3474
Published: Aug. 16, 2024
Language: Английский
Citations
4
Acta Pharmacologica Sinica, Journal Year: 2022, Volume and Issue: 44(5), P. 1066 - 1082
Published: Nov. 14, 2022
Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity its underlying molecular mechanisms. Neuropilin-1 (NRP1) is co-receptor involved in several cellular processes associated chemoresistance development. Since both double-edged process autophagy and hypoxia-derived response play crucial roles loss effectiveness, herein we investigated interplay among NRP1, hypoxia development resistance HCC cell lines. We first analyzed NRP1 expression levels human samples from public databases, found significantly increased well correlation with advanced tumor metastasis stages. Among 3 lines (HepG2, Huh-7 Hep3B), Hep3B cells showed migration ability together higher susceptibility lenvatinib. demonstrated that gene silencing enhanced anticancer effects on cells. Furthermore, suppressed through promoting cells; co-treatment bafilomycin A1 attenuated antitumor lenvatinib, prevented this vitro effectiveness even presence A1. In addition, exposure hypoxic microenvironment decreased Under hypoxia, HIF-1α directly modulated expression; not only combined but also caused by A1, highlighting potential role HIF-1α-derived adaptive acquisition modulation. Overall, may constitute target prevent derived hypoxia-associated modulation HCC.
Language: Английский
Citations
19
Journal of Hepatocellular Carcinoma, Journal Year: 2023, Volume and Issue: Volume 10, P. 1069 - 1083
Published: July 1, 2023
Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for treatment advanced hepatocellular carcinoma (aHCC). Since REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), monotherapy has been widely used aHCC. Moreover, combination therapy, especially combined with immune checkpoint inhibitors (ICIs), shown more encouraging clinical results. However, drug development and comprehensive have not significantly improved prognosis, resistance often encountered treatment. The underlying molecular mechanism still unclear, studies solve are ongoing. mechanisms patients aHCC include regulation signaling pathways, noncoding RNAs, impact microenvironment, tumor stem cell activation other mechanisms. This review aims (1) summarize progress treating aHCC, (2) delineate known current (3) describe therapeutic methods intended overcome these
Language: Английский
Citations
10
Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217472 - 217472
Published: Jan. 1, 2025
Language: Английский
Citations
0
International Journal of Immunopathology and Pharmacology, Journal Year: 2025, Volume and Issue: 39
Published: Jan. 1, 2025
Objective: This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance hepatocellular carcinoma. Methods: Bioinformatics tools and drug sensitivity assays were used association between expression level carcinoma cell lines. Cell function experiments had performed after treatment with and/or a selective inhibitor (MLN-8237). CircRNA microarray, RIP, RNA pull-down, dual-luciferace reporter assay identify downstream molecular mechanism dysregulation. Results: was positively correlated cells. The MLN-8237, combination lenvatinib, synergistically inhibited proliferation vitro vivo, suggesting might be potential therapeutic target for resistance. Mechanistically, induced FGFR1 through hsa-circ-0058046/miR-424-5p/FGFR1 axis. promotes axis simultaneous inhibition by MLN-8237 overcame Conclusion: Collectively, our findings indicate that (HCC) These results suggest may serve as HCC patients exhibiting Furthermore, shows clinical trials at overcoming
Language: Английский
Citations
0
Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)
Published: May 7, 2025
Abstract Background Lenvatinib, a tyrosine kinase receptor inhibitor, has emerged as frontline therapeutic strategy for the management of advanced hepatocellular carcinoma (HCC). However, modest response rate observed with lenvatinib and rapid emergence chemoresistance highlight urgent need to elucidate underlying molecular mechanisms. Herein we aimed at identifying mechanisms resistance in HCC investigated efficacy targeted combination therapies surmount this chemoresistance. Methods We utilized CRISPR/Cas9 gene knockout screening combined transcriptome sequencing lenvatinib-resistant cell lines identify resistance-associated genes. PDGFRA overexpression was validated human cells. further corroborated vitro vivo role using avapritinib, employing mouse orthotopic model, patient-derived organoids (PDO), xenografts (PDX). The association between expression patient prognosis also assessed. Mechanistic studies were conducted signaling pathways contributing mediated by PDGFRA. Results identified key determinant lenvatinib-resistance Consistently, ectopic PGDGFRA conferred upon Treatment inhibitor avapritinib sensitized cells HCC, PDO, PDX models. Increased correlated poor patients. revealed that treatment or promoted through PTEN/AKT/GSK-3β/β-catenin pathway. Conclusions Our findings demonstrate mediates targeting surmounts resistance. Furthermore, pathway implicated resistance, providing potential patients displaying Further clinical are warranted validate these explore application PDGFRA-targeted treatment.
Language: Английский
Citations
0
Expert Review of Molecular Diagnostics, Journal Year: 2021, Volume and Issue: 21(11), P. 1147 - 1164
Published: Sept. 28, 2021
Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib, ramucicurab, nivilumab, pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, drug resistance require clinically applicable validated predictive biomarkers.Areas covered: Our review covers advancements in identification proteomic/genomic/epigenomic/transcriptomic biomarkers predicting HCC treatment efficacy with use multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, immune checkpoint (ICIs). Alpha-fetoprotein, des-carboxyprothrombin, vascular endothelial growth factor, angiopoietin-2, dysregulated MTOR, VEGFR2, c-KIT, RAF1, PDGFRβ potential proteomic/genomic sorafenib treatment. Alanine aminotransferase, aspartate albumin-bilirubin grade can predict other MKIs. Rb, p16, Ki-67, genes involved cell cycle regulation, CDK1-4, CCND1, CDKN1A, CDKN2A proposed CD4/6 while TERT, CTNNB1, TP53 FGF19, are found to be predictors ICI efficacy.Expert opinion: There still limited identify patients who benefit from therapy. Further prospective biomarker validation studies personalized required.
Language: Английский
Citations
23
BioScience Trends, Journal Year: 2023, Volume and Issue: 17(2), P. 136 - 147
Published: Feb. 23, 2023
Hepatic forkhead box protein A2 (FOXA2) is a crucial transcription factor for liver development and metabolic homeostasis. However, its role in hepatocellular carcinoma (HCC) progression lenvatinib-related drug resistance remains unknown. In this study, the level of FOXA2 expression was found to be lower HCC tissues than paired adjacent tumor tissues. A low associated with aggressive characteristics (vascular invasion poor differentiation). an independent risk recurrence (hazard ratio (HR): 1.899, P < 0.001) long-term survival (HR: 2.011, = 0.003) patients after hepatectomy. xenograft animal models, overexpression significantly inhibited growth. Moreover, enhance inhibitory effect lenvatinib on cells by upregulating adenosine monophosphate-activated kinase-mechanistic target rapamycin (AMPK-mTOR) pathway. Conversely, inhibition kinase (AMPK) or stimulation mechanistic (mTOR) attenuated sensitization overexpressing lenvatinib. Similarly, augmented antitumor models tumors. increased autophagy treated Lenvatinib treatment activated platelet-derived growth receptor-extracellular regulated (PDGFR-ERK) pathway HCC. further downregulated PDGFR-ERK through activation AMPK-mTOR axis. conclusion, identified as closely biological By modulating AMPK-mTOR-autophagy signaling pathway, FOX2
Language: Английский
Citations
9