RESUMO
The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.
Assuntos
Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Proteínas de Membrana , Mitoxantrona , Nucleotidiltransferases , Fator de Transcrição STAT3 , Mitoxantrona/farmacologia , Mitoxantrona/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Fator de Transcrição STAT3/metabolismo , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Benzofuranos , NaftoquinonasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (G. lucidum) has been widely used as adjuvant of anti-tumor therapy for variety tumors. The bioactive ingredients of G. lucidum mainly include triterpenes, such as Ganoderic acid A, Ganoderic acid B, Ganoderenic acid A, Ganoderenic acid B, Ganoderenic acid D, and Ganoderic acid X. However, the effects and underlying mechanisms of G. lucidum are often challenging in hepatocellular carcinoma (HCC) treatment. AIM OF THE STUDY: To explore the potential role and mechanism of enhancer-associated lncRNAs (en-lncRNAs) in G. lucidum treated HCC through the in vivo and in vitro experiments. MATERIALS AND METHODS: Hepa1-6-bearing C57 BL/6 mice model were established to evaluate the therapeutic efficacy of G. lucidum treated HCC. Ki67 and TUNEL staining were used to detect the tumor cell proliferation and apoptosis in vivo. The Mouse lncRNA 4*180K array was implemented to identify the differentially expressed (DE) lncRNAs and mRNAs of G. lucidum treated tumor mice. The constructed lncRNA-mRNA co-expression network and bioinformatics analysis were used to selected core en-lncRNAs and its neighboring genes. The UPLC-MS method was used to identify the triterpenes of G. lucidum, and the in vitro experiments were used to verify which triterpene monomers regulated en-lncRNAs in tumor cells. Finally, a stable knockdown/overexpression cell lines were used to confirm the relationship between en-lncRNA and neighboring gene. RESULTS: Ki67 and TUNEL staining demonstrated G. lucidum significantly inhibited tumor growth, suppressed cell proliferation and induced apoptosis in vivo. Transcriptomic analysis revealed the existence of 126 DE lncRNAs high correlated with 454 co-expressed mRNAs in G. lucidum treated tumor mice. Based on lncRNA-mRNA network and qRT-PCR validation, 6 core lncRNAs were selected and considered high correlated with G. lucidum treatment. Bioinformatics analysis revealed FR036820 and FR121302 might act as enhancers, and qRT-PCR results suggested FR121302 might enhance Popdc2 mRNA level in HCC. Furthermore, 6 main triterpene monomers of G. lucidum were identified by UPLC-MS method, and in vitro experiments showed FR121302 and Popdc2 were significantly suppressed by Ganoderenic acid A and Ganoderenic acid B, respectively. The knock/overexpression results demonstrated that FR121302 activating and enhancing Popdc2 expression levels, and Ganoderenic acid A and Ganoderenic acid B dramatically suppressed FR121302 and decreased Popdc2 level in Hepa1-6 cells. CONCLUSIONS: Enhancer-associated lncRNA plays a crucial role as an enhancer during hepatocarcinogenesis, and triterpenes of G. lucidum significantly inhibited tumor cell proliferation and induced apoptosis by regulating en-lncRNAs. Our study demonstrated Ganoderenic acid A and Ganoderenic acid B suppressed en-lncRNA FR121302 may be one of the critical strategies of G. lucidum inhibit hepatocellular carcinoma growth.
Assuntos
Apoptose , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Camundongos Endogâmicos C57BL , RNA Longo não Codificante , Reishi , Triterpenos , Animais , Triterpenos/farmacologia , Triterpenos/isolamento & purificação , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Reishi/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificaçãoRESUMO
Background: The first-line treatment for advanced hepatocellular carcinoma has evolved significantly. This study aimed to identify the most beneficial regimen. Methods: A systematic search was conducted from July 2012 to August 2024 across the following four databases: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. This search focused on phase III prospective randomized controlled trials that compared first-line treatment for advanced hepatocellular carcinoma. Results: Seventeen studies involving 10322 patients were included in this network meta-analysis. Of the studies we included, twelve studies were global multicenter clinical studies, four were initiated in China, and one was initiated in Korea. The results of our statistical analysis suggest that Hepatic artery infusion chemotherapy with oxaliplatin plus fluorouracil (HAIC-FO) demonstrated significant overall survival (OS) benefits compared with most treatments, including various immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). In terms of OS, HAIC had shown similar efficacy with sorafenib plus FOLFOX (HR, 0.88; 95% CI: 0.37-2.09) and transcatheter arterial chemoembolization (TACE) combined with lenvatinib (HR, 0.69; 95% CI: 0.30-1.56). Notably, immune-related treatments, such as ICIs combined with anti-VEGF therapies, also showed improved OS compared with anti-VEGF-TKIs alone. In terms of progression-free survival (PFS), HAIC-FO outperformed anti-VEGF-TKI monotherapy, ICI monotherapy, and several ICI combinations. However, it was not superior to lenvatinib plus TACE or lenvatinib plus pembrolizumab. Based on the Surface Under the Cumulative Ranking Curve (SUCRA) values, HAIC-FO was ranked the most effective in terms of OS (SUCRA = 0.961) and objective response rate (ORR) (SUCRA = 0.971). The results of the subgroup analysis suggested that HAIC-FO achieved the best OS benefit in the macrovascular invasion (MVI) and extrahepatic spread (EHS) subgroup (SUCRA = 0.99) and that tremelimumab combined with durvalumab achieved the best OS benefit in the Asian subgroup (SUCRA = 0.88). Conclusion: This systematic review and network meta-analysis suggest that HAIC-based therapies may become a potential first-line treatment option for advanced HCC, especially for patients in Mainland China with MVI and EHS. Additionally, immune-related treatments may be more suitable for Asian populations.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Neoplasias Hepáticas , Metanálise em Rede , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversosRESUMO
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, particularly when diagnosed at an unresectable stage. Traditional treatments for advanced HCC have limited efficacy, prompting the exploration of combination therapies. This systematic review and meta-analysis evaluate the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in patients with unresectable HCC. Methods: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, including studies up to June 2024. Randomized controlled trials (RCTs) comparing combination therapy (PD-1/PD-L1 inhibitors with anti-angiogenic agents) to monotherapy or standard treatments in unresectable HCC patients were included. Data were synthesized using random-effects models, with pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs). Results: Five Phase III RCTs involving 1515 patients were included. Combination therapy significantly improved OS (HR: 0.71, 95% CI: 0.60-0.85) and PFS (HR: 0.64, 95% CI: 0.53-0.77) compared to monotherapy or standard treatments. The pooled OR for ORR was 1.27 (95% CI: 1.57-2.11), indicating a higher response rate with combination therapy. However, the risk of AEs was also higher in the combination therapy group (RR: 1.04, 95% CI: 1.02-1.06). Subgroup analyses revealed consistent benefits across different types of PD-1/PD-L1 inhibitors and anti-angiogenic agents, with no significant publication bias detected. Conclusions: The combination of PD-1/PD-L1 inhibitors with anti-angiogenic agents offers significant benefits in improving OS and PFS in patients with unresectable HCC, although it is associated with an increased risk of adverse events.
Assuntos
Inibidores da Angiogênese , Antígeno B7-H1 , Carcinoma Hepatocelular , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: This study assessed the cost-effectiveness of radiofrequency ablation compared with percutaneous ethanol injection in patients with early hepatocellular carcinoma in relation to the objective response rate and costs related to the procedure. METHODS: This was a prospective single-center randomized trial. The primary outcome was cost-effectiveness. Secondary outcomes were the complete response rate according to the modified response evaluation criteria in solid tumors 60 days after randomization and the complication rate within 180 60 days. RESULTS: Fifty patients were placed into the following groups: percutaneous ethanol injection (n=23) and radiofrequency ablation (n=27). Fifty-four nodules were randomized (mean follow-up: 205.37 days). The estimated mean hospital cost was US$ 1854.11 and US$ 2770.96 for the Radiofrequency Ablation and Percutaneous Ethanol Injection Groups, respectively. The incremental cost-effectiveness ratio was US$ -2674.59, which is advantageous for radiofrequency ablation. After 60 d, 28 of 29 nodules in the Radiofrequency Ablation Group achieved complete response versus 12 of 22 in the Percutaneous Ethanol Injection Group (RD, 42.01 [95%CI= 20.55-63.24]; p<0.001). Only four early complications were observed among patients treated by percutaneous ethanol injection (p<0.05). Late complications occurred in two and one patient(s) in the Radiofrequency Ablation and Percutaneous Ethanol Injection Groups (p>0.05), respectively. CONCLUSION: Radiofrequency ablation was more cost-effective and achieved higher complete response and lower complication rates than the Percutaneous Ethanol Injection Group within this cohort. REGISTRY OF CLINICAL TRIALS: NCT06450613.
Assuntos
Carcinoma Hepatocelular , Análise Custo-Benefício , Etanol , Neoplasias Hepáticas , Ablação por Radiofrequência , Humanos , Etanol/administração & dosagem , Etanol/economia , Neoplasias Hepáticas/economia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Carcinoma Hepatocelular/economia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Idoso , Ablação por Radiofrequência/economia , Ablação por Radiofrequência/métodos , Injeções Intralesionais/economia , Ablação por Cateter/economia , Ablação por Cateter/métodosRESUMO
PURPOSE: To compare the efficacy of first-line regimens based on programmed cell death (or ligand) [PD-(L)1] blockade in extensive-stage small-cell lung cancer (ES-SCLC) patients with or without liver metastases (LM), and to identify optimal treatment strategies. METHODS: Network meta-analysis of randomized controlled trials (RCTs) comparing chemo-immunotherapy (CIT) and chemotherapy (CT) in ES-SCLC patients stratified by LM. Overall survival (OS) and progression-free survival (PFS) were evaluated using hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Seven RCTs involving 3658 ES-SCLC patients (1243 with LM, 2415 without LM) were analyzed. For patients with LM, the combination therapies of anti-PD-1 + CT (HR, 0.67; 95% CI, 0.54%-0.82%; p < 0.001) and anti-PD-L1 + CT + anti-angiogenesis (HR, 0.84; 95% CI, 0.71%-0.99%; p = 0.042) demonstrated superior efficacy in prolonging OS compared to CT alone. The anti-PD-1 + CT regimen had the highest cumulative probability of 91.6% for extending OS in patients with LM. For patients without LM, all CIT regimens resulted in improved OS compared to CT alone, with the regimen of anti-angiogenesis + anti-PD-L1 + CT ranking first and having the highest cumulative probability of 95.5% for prolonging OS. CONCLUSIONS: CIT is effective for ES-SCLC patients regardless of LM status. For patients with LM, PD-1 blockade combined with CT is the best option. For patients without LM, the most beneficial regimen is the combination of anti-angiogenesis, PD-L1 blockade, and CT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas , Neoplasias Pulmonares , Metanálise em Rede , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estadiamento de Neoplasias , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Immunotherapy presents both promises and challenges in treating hepatocellular carcinoma (HCC) due to its complex immunological microenvironment. The role of B cells, a key part of the immune system, remains uncertain in HCC. AIM: To identify B-cell-specific signatures and reveal novel immunophenotyping and therapeutic targets for HCC. METHODS: Using the Tumor Immune Single-cell Hub 2 database, we identified B-cell-related genes (BRGs) in HCC. Gene enrichment analysis was performed to explore the possible collaboration between B cells and T cells in HCC. We conducted univariate Cox regression analysis using The Cancer Genome Atlas liver HCC collection dataset to find BRGs linked to HCC prognosis. Subsequently, least absolute shrinkage and selection operator regression was utilized to develop a prognostic model with 11 BRGs. The model was validated using the International Cancer Genome Consortium dataset and GSE76427. RESULTS: The risk score derived from the prognostic model emerged as an independent prognostic factor for HCC. Analysis of the immune microenvironment and cell infiltration revealed the immune status of various risk groups, supporting the cooperation of B and T cells in suppressing HCC. The BRGs model identified new molecular subtypes of HCC, each with distinct immune characteristics. Drug sensitivity analysis identified targeted drugs effective for each HCC subtype, enabling precision therapy and guiding clinical decisions. CONCLUSION: We clarified the role of B cells in HCC and propose that the BRGs model offers promising targets for personalized immunotherapy.
Assuntos
Linfócitos B , Carcinoma Hepatocelular , Imunofenotipagem , Neoplasias Hepáticas , Microambiente Tumoral , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamento farmacológico , Microambiente Tumoral/imunologia , Imunofenotipagem/métodos , Prognóstico , Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Masculino , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , Feminino , Linfócitos T/imunologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodosRESUMO
This editorial examines the therapeutic potential of traditional Chinese medicine (TCM) for aggressive cancers, particularly liver cancer. It highlights the study by Huang et al, which shows how Calculus bovis, a component of the TCM Pien Tze Huang, suppresses liver cancer by inhibiting M2 macrophage polarization via the Wnt/ß-catenin pathway. This research emphasizes the importance of transitioning from effective TCM formulations to isolating active components and understanding their mechanisms. While the study provides valuable insights, it primarily focuses on the Wnt/ß-catenin pathway and does not delve deeply into the mechanisms of individual components. Future research should aim to comprehensively study these components, explore their interactions, and validate findings through clinical trials. This approach will integrate traditional wisdom with modern scientific validation, advancing the development of innovative cancer treatments based on TCM formulations.
Assuntos
Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Medicina Tradicional Chinesa , Humanos , Medicina Tradicional Chinesa/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologiaRESUMO
The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.
Assuntos
Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Enterococcus faecium , Ferroptose , Interferon gama , Neoplasias Hepáticas , Sorafenibe , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/microbiologia , Interferon gama/metabolismo , Interferon gama/imunologia , Humanos , Enterococcus faecium/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Animais , Ferroptose/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Probióticos/farmacologia , Masculino , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologiaRESUMO
Hepatic, biliary, and pancreatic cancer pose significant challenges in the field of digestive system diseases due to their highly malignant nature. Traditional Chinese medicine (TCM) has gained attention as a potential therapeutic approach with long-standing use in China and well-recognized clinical benefits. In this review, we systematically summarized the clinical applications of TCM that have shown promising results in clinical trials in treating hepatic, biliary, and pancreatic cancer. We highlighted several commonly used TCM therapeutics with validated efficacy through rigorous clinical trials, including Huaier Granule, Huachansu, and Icaritin. The active compounds and their potential targets have been thoroughly elucidated to offer valuable insights into the potential of TCM for anti-cancer drug discovery. We emphasized the importance of further research to bridge the gap between TCM and modern oncology, facilitating the development of evidence-based TCM treatment for these challenging malignancies.
Assuntos
Descoberta de Drogas , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Medicina Tradicional Chinesa , Humanos , Medicina Tradicional Chinesa/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , AnimaisRESUMO
BACKGROUND: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV-HCC) has poor prognosis and high mortality rate. Euphorbia helioscopia L. (EHL) is a classic Chinese medicinal herb. AIM: This study aimed to evaluate in vitro anti-HBV-HCC properties of EHL, and explore it targets in HBV-HCC based on molecular docking. METHODS: The anti-tumor effect of EHL on HBV-HCC was evaluated using the cell viability, migration, invasion, and apoptosis of Hep 3B2.1-7 and HepG2.2.15 cells. Next, network pharmacological analysis was performed to predicted the key targets of EHL against HBV-HCC. Then the prognostic targets, including RAC-alpha serine/threonine-protein kinase (AKT1) and Caspase-3 (CASP3), were verified using molecular docking and rescue experiments. RESULTS: EHL exhibited inhibitory effects on cell proliferation/migration/invasion and induced cell apoptosis. Network pharmacological analysis proposed 12 active compounds in EHL, which targeted 22 HBV-HCC-related genes. AKT1 and CASP3 were identified to be key targets for EHL against HBV-HCC. AKT1 and CASP3 had prognostic significance in liver cancer. Overexpression of AKT1 and caspase-3 inhibitor can counteract the EHL effect. CONCLUSION: EHL can exert anticancer effects on HBV-HCC by inhibiting migration/invasion, and inducing apoptosis, which may be achieved through AKT1 and CASP3.
Assuntos
Carcinoma Hepatocelular , Caspase 3 , Euphorbia , Vírus da Hepatite B , Neoplasias Hepáticas , Simulação de Acoplamento Molecular , Extratos Vegetais , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Euphorbia/química , Caspase 3/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Hep G2 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hepatite B/virologia , Hepatite B/tratamento farmacológico , Hepatite B/complicaçõesRESUMO
An 84-year-old woman underwent laparoscopic partial hepatectomy for a single 3.0-cm-diameter nodule of hepatocellular carcinoma at segment 5. Although the postoperative condition was uneventful, multiple recurrences were observed six months after hepatic resection. Transcatheter arterial chemoembolization (TACE) was the second-line therapy. However, she was later diagnosed as TACE refractory due to residual tumor and presence of portal vein tumor thrombus. Third-line therapy was the combination of atezolizumab and bevacizumab, which was discontinued after 22 courses due to disease progression. Two months after the conclusion of chemotherapy, sudden onset of purpura was observed around her eyes and on her lower legs. Laboratory tests revealed severe thrombocytopenia, and she was diagnosed with secondary immune thrombocytopenic purpura. Steroids and immunoglobulin therapy were then administered. Although the immature platelet fraction increased after treatment, the platelet count did not. The patient died of intracranial hemorrhage 10 days after initiation of steroid and immunoglobulin therapy.
Assuntos
Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma Hepatocelular , Neoplasias Hepáticas , Púrpura Trombocitopênica Idiopática , Humanos , Feminino , Neoplasias Hepáticas/tratamento farmacológico , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Evolução Fatal , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/diagnóstico por imagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0-37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70-150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control.
Assuntos
Quimioembolização Terapêutica , Doxorrubicina , Sistemas de Liberação de Medicamentos , Microbolhas , Ultrassonografia , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Quimioembolização Terapêutica/métodos , Ultrassonografia/métodos , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Imagens de Fantasmas , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , MicroesferasRESUMO
Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N6-methyladenosine (m6A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m6A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8+ T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m6A-dependent manner, regulating the interplay between CD8+ T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.
Assuntos
Linfócitos T CD8-Positivos , Quimiocina CX3CL1 , Hepatócitos , Neoplasias Hepáticas , Oxaliplatina , Proteínas de Ligação a RNA , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/genética , Hepatócitos/metabolismo , Camundongos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Humanos , Oxaliplatina/farmacologia , Microambiente Tumoral/imunologia , Camundongos Knockout , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Antineoplásicos/farmacologiaRESUMO
An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K+ outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising.
Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Canais de Potássio Ativados por Cálcio de Condutância Intermediária , Neoplasias Hepáticas , Sistema de Sinalização das MAP Quinases , Telomerase , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Telomerase/metabolismo , Telomerase/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos , Masculino , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Nus , Apoptose/efeitos dos fármacos , Feminino , Progressão da Doença , Camundongos Endogâmicos BALB C , Nanopartículas/química , Pessoa de Meia-IdadeRESUMO
Hepatocellular carcinoma (HCC) is caused by various factors including toxic substances and xenobiotics. Numerous treatment strategies are used to address toxicity to the liver and HCC, yet their adverse effects are drawbacks. This study aimed to assess the effect of DEN/CCl4 on morphological changes in the liver, body weight, tumor incidence, and hematological tumor incidence, hematological parameters, hepatic markers, and histopathological analysis in mice following a preventive measure by using ß-caryophyllene (BCP). Adult Balb/c mice were administered a single dose of DEN 1-mg/kg body weight and 0.2-mL CCl4/kg body weight intraperitoneal twice a week (i.p.) for 22 weeks. BCP was treated in one group of mice at 30-mg/kg body weight, intraperitoneal, for 7 weeks. BCP alone was treated in one group of mice at 300-mg/kg body weight intraperitoneal for 22 weeks. DEN/CCl4 caused a reduction in mice's body weight, which was significantly attenuated by BCP administration. BCP supplementation attenuated the tumor incidence DEN/CCl4 (100%) to about 25%. DEN/CCl4 caused alterations in the hematological parameters, serum total protein albumin globulin, A/G ratio, liver function markers (AST, ALT, ALP, GGT, ACP, and bilirubin), and lipid profile markers that were significantly reinstated by BCP administration. Oxidative stress markers (MDA, SOD, CAT, NO, LDH, and GST) were reduced by DEN/CCl4, which were significantly increased in BCP-treated groups. The liver histopathology alterations caused by DEN/CCl4 were amended considerably by BCP treatment. Immunohistochemical studies suggest that AFP, caspase-3, and COX-2 were chronically overexpressed in DEN/CCl4-exposed mice, notably attenuated by BCP administration. BCP suppressed tumor incidence by downregulating inflammation and inducing caspase-3-mediated apoptosis. Conclusively, BCP appears to be a potent natural supplement capable of repressing liver inflammation and carcinoma through the mitigation of oxidative stress and inflammation pathways.
Assuntos
Carcinoma Hepatocelular , Inflamação , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Sesquiterpenos Policíclicos , Animais , Sesquiterpenos Policíclicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/prevenção & controle , Carcinoma Hepatocelular/induzido quimicamente , Masculino , Regulação para Baixo/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/tratamento farmacológico , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos dos fármacos , Tetracloreto de Carbono/toxicidadeRESUMO
BACKGROUND: The treatment of unresectable hepatocellular carcinoma (uHCC) challenging due to unfulfilled clinical requirements. OBJECTIVE: To evaluate the safety and efficacy of combining transarterial chemoembolization (TACE) with sintilimab and lenvatinib in the treatment of uHCC. METHODS: We retrospectively analyzed the data of patients with uHCC who were treated with a combination of TACE, sintilimab, and lenvatinib between May 2019 and December 2021 at the Chinese PLA General Hospital. Systemic treatment was started 1 week after TACE was performed. Sintilimab was administered intravenously at a dosage of 200 mg every three weeks, and lenvatinib was given orally at dosages of 8 mg or 12 mg daily, contingent upon the weight of the patients. The primary endpoint was the objective response rate (ORR) as per the mRECIST. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (tr-AEs). RESULTS: A total of 32 patients were enrolled in the study. Among them, 9 patients were classified as Barcelona Clinic Liver Cancer-B (BCLC-B), 23 patients were classified as BCLC-C, 14 patients diagnosed with portal vein tumors, and 12 patients were diagnosed with extra hepatic metastases. The ORR and DCR were 75% and 90.6% respectively, with 4 patients exhibiting (12.5%) complete response, 20 patients exhibiting (62.5%) partial response, 5 patients exhibiting (15.6%) stable disease, and 3 patients exhibiting (9.4%) progressive disease. With a median follow-up time of 19.6 months, the median PFS was 9.9 months, and the median OS was 33.3 months. A total of 31 patients experienced different degrees of tr-AEs, of which 2 were grade 3 tr-AEs. CONCLUSION: The combination therapy of TACE, sintilimab, and lenvatinib demonstrates satisfactory efficacy in the treatment of uHCC with manageable tr-AEs.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Masculino , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Quimioembolização Terapêutica/métodos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , AdultoRESUMO
This research explored the mechanism of ganoderic acid X(GAX) on human hepatocellular carcinoma cell models(HepG2, HuH6) and nonobese diabetic-severe combined immune deficient(NOD-SCID) mouse subcutaneous tumor models using proteomics, aiming to provide a basis for the clinical application of GAX. CCK-8 assay was employed to evaluate the effect of GAX on the viability of HepG2 and HuH6 cells. EdU assay was used to assess the effect of GAX on cell proliferation. Scratch assay was used to examine the effect of GAX on cell migration ability. Hoechst 33258 staining was used to investigate the effect of GAX on cell apoptosis. Moreover, a NOD-SCID mouse subcutaneous tumor model was established to analyze the tumor volume and weight in control group and GAX low-, medium-, and high-dose groups(5, 10, and 20 mg·kg~(-1)). HE staining was conducted to evaluate the drug toxicity of GAX. Additionally, HepG2 cells in the control group and the GAX high-dose group were subjected to label-free proteomics analysis to identify differential proteins and enrich relevant signaling pathways. CYTO-ID® staining was performed to detect autophagy, and Western blot was conducted to measure the expression levels of relevant proteins. In vitro results demonstrated that GAX dose-depen-dently inhibited proliferation, migration, and induced apoptosis in HepG2 and HuH6 cells. In vivo studies showed that GAX significantly inhibited tumor volume and weight without causing significant damage to major organs(heart, liver, spleen, lung, and kidney) in mice. Label-free proteomics analysis revealed that GAX participated in multiple signaling pathways during the treatment of hepatocellular carcinoma, with a high enrichment in the autophagy pathway. CYTO-ID® staining and Western blot results showed that GAX induced autophagy, upregulated the expression of Beclin-1, ATG5, and LC3-â ¡ proteins, and downregulated the expression of p62 protein. This study suggests that GAX inhibits the proliferation, migration, and induces apoptosis of hepatocellular carcinoma cells by inducing autophagy, thereby significantly inhibiting tumor growth. GAX represents a promising adjuvant therapy for cancer treatment.
Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Hepatoblastoma , Neoplasias Hepáticas , Proteômica , Humanos , Animais , Camundongos , Hepatoblastoma/tratamento farmacológico , Hepatoblastoma/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos SCID , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Camundongos Endogâmicos NOD , Células Hep G2 , Masculino , TriterpenosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) remains a significant global medical challenge. Formononetin, an isoflavone derived from Astragalus membranaceus, has been shown to have various regulatory effects on HCC. However, the exact molecular mechanism by which formononetin acts against HCC is still unclear. PURPOSE: To elucidate the molecular mechanism of formononetin in treating HCC. METHODS: The potential targets of formononetin were retrieved from Swisstargets and SEA databases, while targets associated with HCC were sourced from GeneCards, NCBI and DisGeNET databases. The overlapping targets were visualized using protein-protein interaction (PPI) network analysis via String database, and subsequently subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking was employed to confirm the interaction between formononetin and key targets. Ultimately, the effectiveness of formononetin on HCC and the signalling pathway with the highest enrichment were confirmed in the HCC tumour-bearing mice. Histopathological changes in tumour tissues were observed using haematoxylin and eosin (HE) staining, while apoptosis of tumour cells in mice was assessed through TdT-mediated dUTP nick end labelling (TUNEL) and immunofluorescence staining. The most enriched signalling pathway was verified using Western blotting and immunohistochemical (IHC) staining. RESULTS: One hundred and ninety-three potential targets related to formononetin, 6980 targets associated with HCC and 156 overlapping targets were obtained from the online public databases. Molecular docking studies demonstrated formononetin's robust interaction with core targets. KEGG enrichment analysis identified 111 signalling pathways, including PI3K/AKT and apoptosis signalling pathways. In vivo experiments demonstrated that formononetin significantly promoted apoptosis of tumour cell in mice, as confirmed by HE, TUNEL and immunofluorescence staining (p < .05). Formononetin was found to decrease the phosphorylation levels of PI3K and AKT, reduce the expression of Bcl-2, and increase the expression of cleaved-Caspase-3 and Bax (p < .05). CONCLUSIONS: Formononetin demonstrates dose-dependent regulatory effects on multiple targets, biological processes and signalling pathways in HCC. The compound can mitigate HCC by enhancing PI3K/AKT-mediated apoptosis of tumour cells.
Assuntos
Apoptose , Carcinoma Hepatocelular , Isoflavonas , Neoplasias Hepáticas , Simulação de Acoplamento Molecular , Transdução de Sinais , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Camundongos , Humanos , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Mapas de Interação de Proteínas , Masculino , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Simulação por Computador , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos NusRESUMO
Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.