BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients...BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients with advanced HCC.Different patterns of treatment responsiveness have been identified in differentiated hepatoblastoma HepG2 cells and metastatic HCC SNU449 cells.AIM To define the long non-codingRNA-microRNA-mRNA(lncRNA-miRNA-mRNA)predicted signatures related to selected hallmarks of cancer(apoptosis,autophagy,cell stress,cell dedifferentiation and invasiveness)in RNAseq studies using Sorafenib-treated HepG2 and SNU449 cells.Various available software analyses allowed us to establish the lncRNA-miRNA-mRNA regulatory axes following treatment in HepG2 and SNU449 cells.METHODS HepG2 and SNU449 cells were treated with Sorafenib(10μmol/L)for 24 hours.Total RNA,including small and long RNA,was extracted with a commercial miRNeasy kit.RNAseq was carried out for the identification of changes in lncRNA-miRNA-mRNA regulatory axes.RESULTS MALAT,THAP9-AS1 and SNGH17 appeared to coordinately regulate miR-374b-3p and miR-769-5p that led to upregulation of SMAD7,TIRARP,TFAP4 and FAXDC2 in HepG2 cells.SNHG12,EPB41 L4A-AS1,LINC01578,SNHG12 and GAS5 interacted with let-7b-3p,miR-195-5p and VEGFA in SNU449 cells.The axes MALAT1/hsamir-374b-3p/SMAD7 and MALAT1/hsa-mir-769-5p/TFAP4 were of high relevance for Sorafenib response in HepG2 cells,whereas PVT1/hsa-miR-195-5p/VEGFA was responsible for the differential response of SNU449 cells to Sorafenib treatment.CONCLUSION Critical lncRNAs acting as sponges of miRNA were identified that regulated mRNA expression,whose proteins mainly increased the antitumor effectiveness of the treatment(SMAD7,TIRARP,TFAP4,FAXDC2 and ADRB2).However,the broad regulatory axis leading to increased VEGFA expression may be related to the side effect of Sorafenib in SNU449 cells.展开更多
Sorafenib(Sora)not only has an inhibitory effect on angiogenesis via indirectly inhibiting tumor growth through antiangiogenesis,but also can inactivate the glutathione peroxidase 4(GPX4)to induce ferroptosis.Nonethel...Sorafenib(Sora)not only has an inhibitory effect on angiogenesis via indirectly inhibiting tumor growth through antiangiogenesis,but also can inactivate the glutathione peroxidase 4(GPX4)to induce ferroptosis.Nonetheless,the therapeutic efficacy is hampered by a plethora of factors,including low bioavailability and tumor microenvironment(TME).Of particular note is the hypoxic and reductive TME,which acts as a significant impediment and poses formidable challenges to attain the most optimal treatment outcomes.Herein,we developed a novel therapeutic platform based on Sora-loaded mesoporous ferromanganese nanoparticles(PMFNs@Sora).PMFNs mimics both catalase and GPX activities.The self-sustained catalase activity enables continuous decomposition of hydrogen peroxide to generate oxygen,which alleviates hypoxia microenvironment.The GPX activity simultaneously amplifies the therapeutic efficacy of Sora.The as-synthesized PMFNs@Sora demonstrates significantly enhanced antitumor effect in vitro through apoptosis-ferroptosis,revealed by Western blot.Furthermore,PMFNs@Sora also showed effective tumor growth inhibition in vivo.This multifunctional nanoplatform offers a promising strategy for modulating the TME and enhancing cancer treatment in clinical application.展开更多
BACKGROUND Lenvatinib and sorafenib are tyrosine kinase inhibitors that are effective in the treatment of unresectable hepatocellular carcinoma(uHCC).The efficacy of which of them is better suited to combine transarte...BACKGROUND Lenvatinib and sorafenib are tyrosine kinase inhibitors that are effective in the treatment of unresectable hepatocellular carcinoma(uHCC).The efficacy of which of them is better suited to combine transarterial chemoembolization(TACE)for the treatment of uHCC is ripe.RESULTS A total of six studies involving 547 patients were included,248 in the TACE-lenvatinib group and 299 in the TACE-sorafenib group.Meta-analysis results showed that TACE-lenvatinib was more effective than TACE-sorafenib in complete response[relative risk(RR)=1.81,95%confidence interval(CI):1.11-2.96,P=0.02],partial response(RR=1.38,95%CI:1.12-1.70,P=0.002),objective response rate(RR=1.47,95%CI:1.24-1.74,P<0.0001)and disease control rate(RR=1.22,95%CI:1.00-1.49,P=0.05).TACE-lenvatinib was significantly lower than TACE-sorafenib in progressive disease rate(RR=0.54,95%CI:0.39-0.74,P=0.002).No significant difference was found in stable disease rate(RR=0.89,95%CI:0.60-1.33,P=0.58)between the two groups.TACE-lenvatinib was significantly more effective than TACE-sorafenib in overall survival(hazard ratio=2.00,95%CI:1.59-2.50,P<0.05)and progression free survival(hazard ratio=2.04,95%CI:1.49-2.86,P<0.05).As regards adverse events,TACE-lenvatinib was better in reducing the incidence of hypertension than TACE-sorafenib,while no significant difference was found in overall adverse events,abdominal pain,fever,fatigue,nausea and vomiting,decreased appetite,liver dysfunction,hand-foot skin reaction,diarrhea,thrombocytopenia,and rash between the two groups.CONCLUSION In patients with uHCC,TACE-lenvatinib induced a better tumor response rate and survival outcome than TACE-sorafenib,while TACE-lenvatinib resulted in a higher incidence of hypertension than TACE-sorafenib.However,these conclusions are derived from currently available medical evidence,and further confirmation by more rigorously designed randomized controlled studies is still needed.展开更多
BACKGROUND The combination of sorafenib with transarterial chemoembolization(TACE)is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma(HCC).AIM To evaluate the efficacy of t...BACKGROUND The combination of sorafenib with transarterial chemoembolization(TACE)is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma(HCC).AIM To evaluate the efficacy of this combined treatment strategy in enhancing overall survival(OS)and progression-free survival(PFS)compared to monotherapies.METHODS A systematic review was conducted following the PRISMA guidelines.A comprehensive search was performed across PubMed,EMBASE,Web of Science,and the Cochrane Library up to May 8,2024.Studies were included if they compared sorafenib plus TACE to sorafenib alone or TACE alone in adults with advanced HCC.Primary outcomes were OS,PFS,response rates,and safety profiles.Data extraction and quality assessment were independently performed by two reviewers.Heterogeneity was assessed using the I^(2)statistic,and a random-effects model was applied for pooling data.Sensitivity analysis and publication bias assessment were also conducted.RESULTS A total of twelve studies involving 1174 patients met the inclusion criteria.Significant heterogeneity was observed for both OS(I^(2)=72.6%,P<0.001)and PFS(I^(2)=83.7%,P<0.001).The combined treatment of sorafenib with TACE significantly improved OS[hazard ratio(HR)=0.60,95%confidence interval(CI):0.44-0.76]and PFS(HR=0.54,95%CI:0.38-0.69).Sensitivity analysis confirmed the robustness of these findings.Funnel plots and Egger's test indicated no significant publication bias.CONCLUSION Sorafenib combined with TACE significantly enhances both OS and PFS in patients with advanced HCC compared to monotherapy.This combination therapy represents a promising approach to improving clinical outcomes in advanced liver cancer.展开更多
BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma(HCC)and portal vein invasion generally have a poor prognosis.This paper presents a patient with super-giant HCC and portal vein invasion,who unde...BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma(HCC)and portal vein invasion generally have a poor prognosis.This paper presents a patient with super-giant HCC and portal vein invasion,who underwent hepatectomy followed by a combination of sorafenib and camrelizumab,resulting in complete remission(CR)for 5 years.CASE SUMMARY A 40-year-old male with compensated hepatitis B-related cirrhosis was diagnosed with HCC,Barcelona Clinic Liver Cancer stage C.Enhanced computed tomography imaging revealed a 152 mm×171 mm tumor in the right liver,invading the portal vein and hepatic vein.Liver function was normal.The patient successfully underwent hepatectomy on July 18,2019.However,by December 2019,HCC recurrence with lung metastases and portal vein invasion were detected.He started treatment with sorafenib(200 mg twice daily)and camrelizumab(200 mg every 3 weeks).By May 12,2020,the patient was confirmed to have CR.Camrelizumab was adjusted to 200 mg every 12 weeks from June 16,2021,with the last infusion on March 29,2024.Although no further tumor recurrence was observed,he experienced two episodes of gastrointestinal bleeding due to esophagogastric varices,which were managed with endoscopic therapy.To date,the patient has remained in CR for 5 years.CONCLUSION The combination of hepatectomy with sorafenib and camrelizumab can achieve durable CR in patients with supergiant HCC and portal vein invasion.Further research is necessary to address these challenges and improve patient outcomes.展开更多
Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic ...Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic stem cell transplantation(allo-HSCT)demonstrated improved survival outcomes,however,some still experienced relapse during the maintenance.This study aimed to explore risk factors which might be indicators for poor survival after allo-HSCT in this population.Methods:We consecutively enrolled FLT3-ITD AML patients undergoing transplantation at three centers.By integrating genetic profiles with clinical information,we assessed their impact on transplant outcomes.Results:A total of 196 patient were eligible in the analysis,among whom 14%harbored myelodysplasia-related(MR)mutations,including ASXL1,BCOR,EZH2,RUNX1,SF3B1,SRSF2,STAG2,U2AF1,and ZRSR2.Co-mutant MR was independently associated with poorer overall survival(OS)[hazard ratio(HR):2.4,95%confidence interval(95%CI):1.1-5.3,P=0.030].DNMT3A co-mutations strongly predicted adverse survival and relapse[OS:HR:2.1,95%CI:1.0-4.3,P=0.045;relapse-free survival(RFS):HR:2.2,95%CI:1.1-4.1,P=0.017;cumulative incidence of relapse(CIR):HR:2.3,95%CI:1.1-4.8,P=0.030].Compared to patients with negative measurable residual disease(MRD)complete remission(CR),no significant differences were observed in CR patients with positive MRD,while those without CR exhibited significantly inferior outcomes(P=0.003).Conclusions:Patients with myelodysplasia-related gene mutations(MRmut)and/or DNMT3A mutations experienced inferior outcomes after transplantation,requiring further exploration.Furthermore,similar prognoses among CR patients highlighted the need for monitoring specific molecular residual lesions.展开更多
Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To ad...Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To address these challenges,IL-2-So-Lipo,a novel liposomal formulation combining IL-2 with sorafenib derivative,was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth.Sorafenib derivatives could target at melanoma-specific receptors,further enhancing liposomal specificity at the tumor site.Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies,as well as their combination.In a B16F10 melanoma model,IL-2-So-Lipo was found to significantly inhibit tumor progression(tumor volume of 108.01±62.99 mm^(3))compared to the control group(tumor volume of 1,397.13±75.55 mm^(3)),improving the therapeutic efficacy.This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes.Additionally,liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency,promoting tumor cell apoptosis and suppressing angiogenesis.Mechanistically,IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype.Furthermore,IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway,exerting a significant role in mediating tumor resistance to sorafenib.These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers.Moreover,the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy,offering a synergistic approach to improve therapeutic outcomes for solid tumors.展开更多
Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficac...Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.Methods:After observing epithelial-mesenchymal transformation(EMT)changes in HepG2 and HepG2/Sorafenib cells,we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC.Subsequently,specific inhibitors of c-Jun N-terminal kinase(JNK,SP600125)and extracellular signal-regulated kinase(ERK,PD98059)were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor(EGFR)/JNK/ERK signaling pathway in vitro and in vivo.Biological behavior changes were assessed through cell counting kit-8(CCK-8),colony formation,transwell,and immunofluorescence tests.Simultaneously,Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.Results:The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells,and sorafenib-resistant HCC was characterized by EMT changes.Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells,with minimal impact on HepG2 cells.Additionally,apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells.Furthermore,there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups.Notably,SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.Conclusion:Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.展开更多
BACKGROUND Patients with liver cancer complicated by portal hypertension present complex challenges in treatment.AIM To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving live...BACKGROUND Patients with liver cancer complicated by portal hypertension present complex challenges in treatment.AIM To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this condition.METHODS Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group(n=50)and a control group(n=50)according to the treatment regimen.The research group received radiofrequency ablation(RFA)in combination with sorafenib,and the control group only received RFA.The short-term efficacy of both the research and control groups was observed.Liver function and portal hypertension were compared before and after treatment.Alpha-fetoprotein(AFP),glypican-3(GPC-3),and AFP-L3 levels were compared between the two groups prior to and after treatment.The occurrence of adverse reactions in both groups was observed.The 3-year survival rate was compared between the two groups.Basic data were compared between the survival and non-surviving groups.To identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension,multivariate logistic regression analysis was employed.RESULTS When comparing the two groups,the research group's total effective rate(82.00%)was significantly greater than that of the control group(56.00%;P<0.05).Following treatment,alanine aminotransferase and aspartate aminotransferase levels increased,and portal vein pressure decreased in both groups.The degree of improvement for every index was substantially greater in the research group than in the control group(P<0.05).Following treatment,the AFP,GPC-3,and AFP-L3 levels in both groups decreased,with the research group having significantly lower levels than the control group(P<0.05).The incidence of diarrhea,rash,nausea and vomiting,and fatigue in the research group was significantly greater than that in the control group(P<0.05).The 1-,2-,and 3-year survival rates of the research group(94.00%,84.00%,and 72.00%,respectively)were significantly greater than those of the control group(80.00%,64.00%,and 40.00%,respectively;P<0.05).Significant differences were observed between the survival group and the non-surviving group in terms of Child-Pugh grade,history of hepatitis,number of tumors,tumor size,use of sorafenib,stage of liver cancer,histological differentiation,history of splenectomy and other basic data(P<0.05).Logistic regression analysis demonstrated that high Child-Pugh grade,tumor size(6–10 cm),history of hepatitis,no use of sorafenib,liver cancer stage IIIC,and previous splenectomy were independent risk factors for poor prognosis in patients with liver cancer complicated with portal hypertension(P<0.05).CONCLUSION Patients suffering from liver cancer complicated by portal hypertension benefit from the combination of RFA and sorafenib therapy because it effectively restores liver function and increases survival rates.The prognosis of patients suffering from liver cancer complicated by portal hypertension is strongly associated with factors such as high Child-Pugh grade,tumor size(6-10 cm),history of hepatitis,lack of sorafenib use,liver cancer at stage IIIC,and prior splenectomy.展开更多
Objective Mitofusin-2(MFN2)is a mitochondrial membrane protein that plays a critical role in regulating mitochondrial fusion and cellular metabolism.To further elucidate the impact of MFN2,this study aimed to investig...Objective Mitofusin-2(MFN2)is a mitochondrial membrane protein that plays a critical role in regulating mitochondrial fusion and cellular metabolism.To further elucidate the impact of MFN2,this study aimed to investigate its significance on hepatocellular carcinoma(HCC)cell function and its potential role in mediating chemosensitivity.Methods This study investigated the effects of silencing and overexpressing MFN2 on the survival,proliferation,invasion and migration abilities,and sorafenib resistance of MHCC97-L HCC cells.Additional experiments were conducted using XAV939(aβ-catenin inhibitor)and HLY78(aβ-catenin activator)to further validate these findings.Results Silencing MFN2 significantly promoted the survival and proliferation of MHCC97-L cells,enhanced their invasion and migration capacities,increased the IC50 of sorafenib,reduced the percentage of TUNEL-positive cells,and decreased the expression of proapoptotic proteins.Additionally,silencing MFN2 markedly induced the nuclear translocation ofβ-catenin,increasedβ-catenin acetylation levels and enhanced the expression of the downstream regulatory proteins Snail1 and Vimentin while inhibiting E-cadherin expression.Conversely,overexpressing MFN2 reversed the effects observed in MHCC97-L cells mentioned above.The results confirmed that silencing MFN2 activated theβ-catenin/epithelial-mesenchymal transition(EMT)pathway and reduced the sensitivity of cells to sorafenib,which could be reversed by XAV939 treatment.Conversely,overexpression of MFN2 inhibited theβ-catenin/EMT pathway and increased the sensitivity of cells to sorafenib,which could be altered by HLY78.Conclusion Low expression of MFN2 in HCC cells promotes the nuclear translocation ofβ-catenin,thereby activating the EMT pathway and mediating resistance to sorafenib.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a prevalent and aggressive tumor.Sorafenib is the first-line treatment for patients with advanced HCC,but resistance to sorafenib has become a significant challenge in this t...BACKGROUND Hepatocellular carcinoma(HCC)is a prevalent and aggressive tumor.Sorafenib is the first-line treatment for patients with advanced HCC,but resistance to sorafenib has become a significant challenge in this therapy.Cancer stem cells play a crucial role in sorafenib resistance in HCC.Our previous study revealed that the long non-coding RNA(lncRNA)KIF9-AS1 is an oncogenic gene in HCC.However,the role of KIF9-AS1 in drug resistance and cancer stemness in HCC remains unclear.Herein,we aimed to investigate the function and mechanism of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC.AIM To describe the role of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC and elucidate the underlying mechanism.METHODS Tumor tissue and adjacent non-cancerous tissue samples were collected from HCC patients.Sphere formation was quantified via a tumor sphere assay.Cell viability,proliferation,and apoptosis were evaluated via Cell Counting Kit-8,flow cytometry,and colony formation assays,respectively.The interactions between the lncRNA KIF9-AS1 and its downstream targets were confirmed via RNA immunoprecipitation and coimmunoprecipitation.The tumorigenic role of KIF9-AS1 was validated in a mouse model.RESULTS Compared with that in normal controls,the expression of the lncRNA KIF9-AS1 was upregulated in HCC tissues.Knockdown of KIF9-AS1 inhibited stemness and attenuated sorafenib resistance in HCC cells.Mechanistically,N6-methyladenosine modification mediated by methyltransferase-like 3/insulin-like growth factor 2 mRNA-binding protein 1 stabilized and increased the expression of KIF9-AS1.Additionally,KIF9-AS1 increased the stability and expression of short stature homeobox 2 by promoting ubiquitin-specific peptidase 1-induced deubiquitination.Furthermore,depletion of KIF9-AS1 alleviated sorafenib resistance in a xenograft mouse model of HCC.CONCLUSION The N6-methyladenosine-modified lncRNA KIF9-AS1 promoted stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expression.展开更多
Hepatocellular carcinoma(HCC)poses a significant threat to human health.Resistance to sorafenib in the chemotherapy of HCC is a common and significant issue that profoundly impacts clinical treatment.While several membe...Hepatocellular carcinoma(HCC)poses a significant threat to human health.Resistance to sorafenib in the chemotherapy of HCC is a common and significant issue that profoundly impacts clinical treatment.While several members of the transmembrane(TMEM)protein family have been implicated in the occurrence and progression of HCC,the association between TMEM39b and HCC remains unexplored.This study revealed a significant overexpression of TMEM39b in HCC,which correlated with a poor prognosis.Subsequent investigation revealed that RAS-selective lethal 3(RSL3)induced pronounced ferroptosis in HCC,and knocking down the expression of TMEM39b significantly decreased its severity.Similarly,following the induction of ferroptosis in HCC by sorafenib,knocking down the expression of TMEM39b also decreased the severity of ferroptosis,enhancing HCC tolerance to sorafenib.In conclusion,we propose that TMEM39b promotes tumor progression and resistance to sorafenib by inhibiting ferroptosis in HCC.展开更多
Background:Drug-induced liver damage is a severe medical issue that affects people all over the world.Sorafenib has some side effects that cause liver injury.A dietary medicinal plant called Penthorum chinense Pursh.(...Background:Drug-induced liver damage is a severe medical issue that affects people all over the world.Sorafenib has some side effects that cause liver injury.A dietary medicinal plant called Penthorum chinense Pursh.(PCP)has hepatoprotective properties.There are currently few reports on PCP’s protective impact and mechanism against sorafenib-induced liver injury.Methods:To create a liver injury model,sorafenib was administered to BRL-3A cells.Cell viability assays,immunofluorescence tests,Western blotting,real-time quantitative PCR,and high-content imaging systems were utilized to examine PCP’s effect and mechanism.Results:In this study,PCP treatment mitigated the liver damage caused by sorafenib by enhancing cell survival,lowering lipid reactive oxygen species and malondialdehyde levels,and elevating glutathione levels.In addition,PCP can enhance the protein expression of cystine/glutamate transporter xCT and glutathione peroxidase 4,reduce iron content and alleviate mitochondrial toxicity.Further mechanism studies revealed that PCP inhibited ferroptosis by promoting the production of nuclear factor E2-related factor 2 nuclear translocation and subsequently affecting target genes(HO-1 and NQO1).Conclusion:Together,PCP regulates the nuclear factor E2-related factor 2 pathway,which helps to lessen ferroptosis brought on by sorafenib.展开更多
Background:Luteolin is a flavonoid chemical that exists in a variety of medicinal and edible plants and holds many biologically active properties in liver protection,anti-cancer,antioxidants,anti-inflammatory,neuropro...Background:Luteolin is a flavonoid chemical that exists in a variety of medicinal and edible plants and holds many biologically active properties in liver protection,anti-cancer,antioxidants,anti-inflammatory,neuroprotective,etc.According to its hepatoprotective properties,luteolin was selected to co-treat with sorafenib,one of the approved protein kinase inhibitors,to reduce sorafenib-induced normal liver cell damage.Methods:The BRL-3A cell line was treated with sorafenib to establish a liver injury model,followed by luteolin treatment.The cell viability was detected,and the mechanism of action was detected by immunofluorescence,western blotting,and real-time quantitative PCR.Results:The research findings demonstrated that luteolin could increase cystine/glutamate transporter xCT(SLC7A11)and glutathione peroxidase 4(GPX4)expression and display a chelating effect on iron,which led to increased glutathione and decreased malondialdehyde,Fe^(2+) and lipid reactive oxygen species contents in BRL-3A cells,and the sorafenib-induced mitochondrial membrane potential decrease was also inhibited.In addition,when sorafenib caused the accumulation of lipid reactive oxygen species,luteolin could help release this oxidative stress by activating nuclear factor E2-related factor 2(Nrf2)and up-regulating the expression of the associated genes heme oxygenase 1(HO-1)and quinone oxidoreductase 1(NQO1).Conclusion:Therefore,luteolin may ameliorate sorafenib-induced ferroptosis by activating the Nrf2-associated pathway without any impact on sorafenib anti-cancer activity.It can be used as an adjuvant to sorafenib to reduce liver injury in patients with hepatocellular carcinoma.展开更多
BACKGROUND Although the past decade has seen remarkable advances in treatment options for hepatocellular carcinoma(HCC),the dismal overall prognosis still envelops HCC patients.Several comparative trials have been con...BACKGROUND Although the past decade has seen remarkable advances in treatment options for hepatocellular carcinoma(HCC),the dismal overall prognosis still envelops HCC patients.Several comparative trials have been conducted to study whether transarterial chemoembolization(TACE)could improve clinical outcomes in patients receiving sorafenib for advanced HCC;however,the findings have been inconsistent.AIM To study the potential synergies and safety of sorafenib plus TACE vs sorafenib alone for treating advanced HCC,by performing a systematic review and metaanalysis.METHODS This study was conducted following the PRISMA statement.A systematic literature search was conducted using the Cochrane Library,Embase,PubMed,and Web of Science databases.Data included in the present work were collected from patients diagnosed with advanced HCC receiving sorafenib plus TACE or sorafenib alone.Data synthesis and meta-analysis were conducted using Review Manager software.RESULTS The present study included 2780 patients from five comparative clinical trials(1 was randomized control trial and 4 were retrospective studies).It was found that patients receiving sorafenib plus TACE had better prognoses in terms of overall survival(OS),with a combined hazard ratio(HR)of 0.65[95%confidence interval(95%CI):0.46–0.93,P=0.02,n=2780].Consistently,progression free survival(PFS)and time to progression(TTP)differed significantly between the sorafenib plus TACE arm and sorafenib arm(PFS:HR=0.62,95%CI:0.40–0.96,P=0.03,n=443;TTP:HR=0.73,95%CI:0.64-0.83,P<0.00001,n=2451).Disease control rate(DCR)was also significantly increased by combination therapy(risk ratio=1.36,95%CI:1.02-1.81,P=0.04,n=641).Regarding safety,the incidence of any adverse event(AE)was increased due to the addition of TACE;however,no significant difference was found in grade≥3 AEs.CONCLUSION The combination of sorafenib with TACE has superior efficacy to sorafenib monotherapy,as evidenced by prolonged OS,PFS,and TTP,as well as increased DCR.Additional high-quality trials are essential to further validate the clinical benefit of this combination in the treatment of advanced HCC.展开更多
Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditio...Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. The delivery of therapeutic compounds to the target site is a major challenge in the treatment of many diseases. Objective: This study aims to evaluate activated charcoal nanoparticles as a drug delivery system for anticancer agents (Sorafenib and Doxorubicin) in Hepatocellular Cancer Stem Cells. Method: The percent efficiency of entrapment (% EE) of the doxorubicin and sorafenib entrapped onto the activated charcoal was obtained by determining the free doxorubicin and sorafenib concentration in the supernatant-prepared solutions. Then the characterizations of nanoparticles were formed by determination of the particle size distribution, zeta potential, and polydispersity index (PDI). The anticancer activity of activated Charcoal, Doxorubicin-ACNP, sorafenib-ACNP, free doxorubicin, and free sorafenib solutions was measured based on cell viability percentage in HepG2 cell lines (ATCC-CCL 75). In vitro RBC’s toxicity of Doxorubicin/sorafenib loaded charcoal was estimated by hemolysis percentage. Results: The synthesized Doxorubicin-ACNP and Sorafenib-ACNP were evaluated and their physiochemical properties were also examined. Essentially, the percent Efficiency of Entrapment (EE %) was found to be 87.5% and 82.66% for Doxorubicin-ACNP and Sorafenib-ACNP, respectively. The loading capacity was 34.78% and 24.31% for Doxorubicin-ACNP and Sorafenib-ACNP. Using the Dynamic Light scattering [DLS] for the determination of the hydrodynamic size and surface zeta potential, a narrow sample size distribution was obtained of (18, 68, and 190 nm for charcoal, 105, 255, and 712 nm for doxorubicin, and 91, 295, and 955 nm for sorafenib), respectively. A surface charge of −13.2, −15.6 and −17 was obtained for charcoal, doxorubicin/charcoal, and sorafenib/charcoal nanoparticles. The cytotoxic activity of Doxorubicin-ACNP and Sorafenib-ACNP was evaluated in-vitro against HepG2 cell lines and it was observed that Drug loaded ACNP improved anticancer activity when compared to Doxorubicin or Sorafenib alone. Moreover, testing the toxicity potential of DOX-ACNP and Sorafenib-ACNP showed a significant reduction in the hemolysis of red blood cells when compared to Doxorubicin and Sorafenib alone. Conclusion: In conclusion, it is notable to state that this study is regarded as the first to investigate the use of Activated charcoal for the loading of Doxorubicin and Sorafenib for further use in the arena of hepatocellular carcinoma. Doxorubicin-ACNP and Sorafenib-ACNP showed noteworthy anticancer activity along with a reduced potential of RBCs hemolysis rendering it as an efficacious carrier with a low toxicity potential.展开更多
BACKGROUND In the quest to manage hepatocellular carcinoma(HCC),the focus has shifted to a more holistic approach encompassing both data analytics and innovative treatments.Analyzing rich data resources,such as the ca...BACKGROUND In the quest to manage hepatocellular carcinoma(HCC),the focus has shifted to a more holistic approach encompassing both data analytics and innovative treatments.Analyzing rich data resources,such as the cancer genome atlas(TCGA),and examining progressive therapies can potentially reshape the trajectory of HCC treatment.AIM To elucidate the immunological genes and the underlying mechanism of the combined Kombo knife and sorafenib regimen for HCC by analyzing data from TCGA and machine learning data.METHODS Immune attributes were evaluated via TCGA's postablation HCC RNA sequencing data.Using weighted gene coexpression network analysis and machine learning,we identified genes with high prognostic value.The therapeutic landscape and safety metrics of the integrated treatment were critically evaluated across cellular and animal models.RESULTS Immune genes–specifically,peptidylprolyl isomerase A and solute carrier family 29 member 3–emerged as significant prognostic markers.Enhanced therapeutic outcomes,such as prolonged progression-free survival and an elevated overall response rate,characterize the combined approach,with peripheral blood mononuclear cells displaying potent effects on HCC dynamics.CONCLUSION The combination of Kombo knife with sorafenib is an innovative HCC treatment modality anchored in immunecentric strategies.展开更多
基金Supported by Instituto de Salud Carlos III(ISCiii),No.PI19/01266 and No.PI22/00857Consejería de Salud y Familias(Junta de Andalucía),No.PI-0216-2020 and No.PIP-0215-2020Biomedical Research Network Center for Liver and Digestive Diseases(CIBERehd)founded by the ISCIII and co-financed by European Regional Development Fund“A way to achieve Europe”ERDF.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients with advanced HCC.Different patterns of treatment responsiveness have been identified in differentiated hepatoblastoma HepG2 cells and metastatic HCC SNU449 cells.AIM To define the long non-codingRNA-microRNA-mRNA(lncRNA-miRNA-mRNA)predicted signatures related to selected hallmarks of cancer(apoptosis,autophagy,cell stress,cell dedifferentiation and invasiveness)in RNAseq studies using Sorafenib-treated HepG2 and SNU449 cells.Various available software analyses allowed us to establish the lncRNA-miRNA-mRNA regulatory axes following treatment in HepG2 and SNU449 cells.METHODS HepG2 and SNU449 cells were treated with Sorafenib(10μmol/L)for 24 hours.Total RNA,including small and long RNA,was extracted with a commercial miRNeasy kit.RNAseq was carried out for the identification of changes in lncRNA-miRNA-mRNA regulatory axes.RESULTS MALAT,THAP9-AS1 and SNGH17 appeared to coordinately regulate miR-374b-3p and miR-769-5p that led to upregulation of SMAD7,TIRARP,TFAP4 and FAXDC2 in HepG2 cells.SNHG12,EPB41 L4A-AS1,LINC01578,SNHG12 and GAS5 interacted with let-7b-3p,miR-195-5p and VEGFA in SNU449 cells.The axes MALAT1/hsamir-374b-3p/SMAD7 and MALAT1/hsa-mir-769-5p/TFAP4 were of high relevance for Sorafenib response in HepG2 cells,whereas PVT1/hsa-miR-195-5p/VEGFA was responsible for the differential response of SNU449 cells to Sorafenib treatment.CONCLUSION Critical lncRNAs acting as sponges of miRNA were identified that regulated mRNA expression,whose proteins mainly increased the antitumor effectiveness of the treatment(SMAD7,TIRARP,TFAP4,FAXDC2 and ADRB2).However,the broad regulatory axis leading to increased VEGFA expression may be related to the side effect of Sorafenib in SNU449 cells.
基金the financial support by National Natural Science Foundation of China(No.82171997)the Guangdong Basic and Applied Basic Research Fund Foundation(No.2023B1515120073)+2 种基金the Science and Technology Planning Project of Guangdong Province(No.2023B1212060013)Guangzhou Science and Technology Bureau(No.2023A03J0708)Shenzhen Science and Technology Program(Nos.JCYJ20230807111120043,JCYJ20220818102014028)。
文摘Sorafenib(Sora)not only has an inhibitory effect on angiogenesis via indirectly inhibiting tumor growth through antiangiogenesis,but also can inactivate the glutathione peroxidase 4(GPX4)to induce ferroptosis.Nonetheless,the therapeutic efficacy is hampered by a plethora of factors,including low bioavailability and tumor microenvironment(TME).Of particular note is the hypoxic and reductive TME,which acts as a significant impediment and poses formidable challenges to attain the most optimal treatment outcomes.Herein,we developed a novel therapeutic platform based on Sora-loaded mesoporous ferromanganese nanoparticles(PMFNs@Sora).PMFNs mimics both catalase and GPX activities.The self-sustained catalase activity enables continuous decomposition of hydrogen peroxide to generate oxygen,which alleviates hypoxia microenvironment.The GPX activity simultaneously amplifies the therapeutic efficacy of Sora.The as-synthesized PMFNs@Sora demonstrates significantly enhanced antitumor effect in vitro through apoptosis-ferroptosis,revealed by Western blot.Furthermore,PMFNs@Sora also showed effective tumor growth inhibition in vivo.This multifunctional nanoplatform offers a promising strategy for modulating the TME and enhancing cancer treatment in clinical application.
基金Supported by the Shenzhen High-Level Hospital Construction Fund,the Sanming Project of Medicine in Shenzhen,No.SZSM202011010Intramural Research Projects of Shenzhen Hospital,Cancer Hospital,Chinese Academy of Medical Sciences,No.SZ2020MS010the Scientific Research Program Fund of Hunan Provincial Health Commission,No.202204014693.
文摘BACKGROUND Lenvatinib and sorafenib are tyrosine kinase inhibitors that are effective in the treatment of unresectable hepatocellular carcinoma(uHCC).The efficacy of which of them is better suited to combine transarterial chemoembolization(TACE)for the treatment of uHCC is ripe.RESULTS A total of six studies involving 547 patients were included,248 in the TACE-lenvatinib group and 299 in the TACE-sorafenib group.Meta-analysis results showed that TACE-lenvatinib was more effective than TACE-sorafenib in complete response[relative risk(RR)=1.81,95%confidence interval(CI):1.11-2.96,P=0.02],partial response(RR=1.38,95%CI:1.12-1.70,P=0.002),objective response rate(RR=1.47,95%CI:1.24-1.74,P<0.0001)and disease control rate(RR=1.22,95%CI:1.00-1.49,P=0.05).TACE-lenvatinib was significantly lower than TACE-sorafenib in progressive disease rate(RR=0.54,95%CI:0.39-0.74,P=0.002).No significant difference was found in stable disease rate(RR=0.89,95%CI:0.60-1.33,P=0.58)between the two groups.TACE-lenvatinib was significantly more effective than TACE-sorafenib in overall survival(hazard ratio=2.00,95%CI:1.59-2.50,P<0.05)and progression free survival(hazard ratio=2.04,95%CI:1.49-2.86,P<0.05).As regards adverse events,TACE-lenvatinib was better in reducing the incidence of hypertension than TACE-sorafenib,while no significant difference was found in overall adverse events,abdominal pain,fever,fatigue,nausea and vomiting,decreased appetite,liver dysfunction,hand-foot skin reaction,diarrhea,thrombocytopenia,and rash between the two groups.CONCLUSION In patients with uHCC,TACE-lenvatinib induced a better tumor response rate and survival outcome than TACE-sorafenib,while TACE-lenvatinib resulted in a higher incidence of hypertension than TACE-sorafenib.However,these conclusions are derived from currently available medical evidence,and further confirmation by more rigorously designed randomized controlled studies is still needed.
基金Supported by Sichuan Science and Technology Program,No.2022YFS0625。
文摘BACKGROUND The combination of sorafenib with transarterial chemoembolization(TACE)is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma(HCC).AIM To evaluate the efficacy of this combined treatment strategy in enhancing overall survival(OS)and progression-free survival(PFS)compared to monotherapies.METHODS A systematic review was conducted following the PRISMA guidelines.A comprehensive search was performed across PubMed,EMBASE,Web of Science,and the Cochrane Library up to May 8,2024.Studies were included if they compared sorafenib plus TACE to sorafenib alone or TACE alone in adults with advanced HCC.Primary outcomes were OS,PFS,response rates,and safety profiles.Data extraction and quality assessment were independently performed by two reviewers.Heterogeneity was assessed using the I^(2)statistic,and a random-effects model was applied for pooling data.Sensitivity analysis and publication bias assessment were also conducted.RESULTS A total of twelve studies involving 1174 patients met the inclusion criteria.Significant heterogeneity was observed for both OS(I^(2)=72.6%,P<0.001)and PFS(I^(2)=83.7%,P<0.001).The combined treatment of sorafenib with TACE significantly improved OS[hazard ratio(HR)=0.60,95%confidence interval(CI):0.44-0.76]and PFS(HR=0.54,95%CI:0.38-0.69).Sensitivity analysis confirmed the robustness of these findings.Funnel plots and Egger's test indicated no significant publication bias.CONCLUSION Sorafenib combined with TACE significantly enhances both OS and PFS in patients with advanced HCC compared to monotherapy.This combination therapy represents a promising approach to improving clinical outcomes in advanced liver cancer.
文摘BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma(HCC)and portal vein invasion generally have a poor prognosis.This paper presents a patient with super-giant HCC and portal vein invasion,who underwent hepatectomy followed by a combination of sorafenib and camrelizumab,resulting in complete remission(CR)for 5 years.CASE SUMMARY A 40-year-old male with compensated hepatitis B-related cirrhosis was diagnosed with HCC,Barcelona Clinic Liver Cancer stage C.Enhanced computed tomography imaging revealed a 152 mm×171 mm tumor in the right liver,invading the portal vein and hepatic vein.Liver function was normal.The patient successfully underwent hepatectomy on July 18,2019.However,by December 2019,HCC recurrence with lung metastases and portal vein invasion were detected.He started treatment with sorafenib(200 mg twice daily)and camrelizumab(200 mg every 3 weeks).By May 12,2020,the patient was confirmed to have CR.Camrelizumab was adjusted to 200 mg every 12 weeks from June 16,2021,with the last infusion on March 29,2024.Although no further tumor recurrence was observed,he experienced two episodes of gastrointestinal bleeding due to esophagogastric varices,which were managed with endoscopic therapy.To date,the patient has remained in CR for 5 years.CONCLUSION The combination of hepatectomy with sorafenib and camrelizumab can achieve durable CR in patients with supergiant HCC and portal vein invasion.Further research is necessary to address these challenges and improve patient outcomes.
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1103500)the National Natural Science Foundation of China(No.82170210)。
文摘Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic stem cell transplantation(allo-HSCT)demonstrated improved survival outcomes,however,some still experienced relapse during the maintenance.This study aimed to explore risk factors which might be indicators for poor survival after allo-HSCT in this population.Methods:We consecutively enrolled FLT3-ITD AML patients undergoing transplantation at three centers.By integrating genetic profiles with clinical information,we assessed their impact on transplant outcomes.Results:A total of 196 patient were eligible in the analysis,among whom 14%harbored myelodysplasia-related(MR)mutations,including ASXL1,BCOR,EZH2,RUNX1,SF3B1,SRSF2,STAG2,U2AF1,and ZRSR2.Co-mutant MR was independently associated with poorer overall survival(OS)[hazard ratio(HR):2.4,95%confidence interval(95%CI):1.1-5.3,P=0.030].DNMT3A co-mutations strongly predicted adverse survival and relapse[OS:HR:2.1,95%CI:1.0-4.3,P=0.045;relapse-free survival(RFS):HR:2.2,95%CI:1.1-4.1,P=0.017;cumulative incidence of relapse(CIR):HR:2.3,95%CI:1.1-4.8,P=0.030].Compared to patients with negative measurable residual disease(MRD)complete remission(CR),no significant differences were observed in CR patients with positive MRD,while those without CR exhibited significantly inferior outcomes(P=0.003).Conclusions:Patients with myelodysplasia-related gene mutations(MRmut)and/or DNMT3A mutations experienced inferior outcomes after transplantation,requiring further exploration.Furthermore,similar prognoses among CR patients highlighted the need for monitoring specific molecular residual lesions.
基金supported by the Macao Science and Technology Development Fund (FDCT 0148/2022/A3 and 0019/2024/RIA1)the National Natural Science Foundation of China (No. 81572979)
文摘Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To address these challenges,IL-2-So-Lipo,a novel liposomal formulation combining IL-2 with sorafenib derivative,was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth.Sorafenib derivatives could target at melanoma-specific receptors,further enhancing liposomal specificity at the tumor site.Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies,as well as their combination.In a B16F10 melanoma model,IL-2-So-Lipo was found to significantly inhibit tumor progression(tumor volume of 108.01±62.99 mm^(3))compared to the control group(tumor volume of 1,397.13±75.55 mm^(3)),improving the therapeutic efficacy.This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes.Additionally,liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency,promoting tumor cell apoptosis and suppressing angiogenesis.Mechanistically,IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype.Furthermore,IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway,exerting a significant role in mediating tumor resistance to sorafenib.These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers.Moreover,the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy,offering a synergistic approach to improve therapeutic outcomes for solid tumors.
基金supported by Natural Science Foundation of Shandong Province,No.ZR2021QH186National Natural Science Foundation of China,No.81870205+3 种基金Foundation Research Project of Qinghai Province,2021-ZJ-719National Natural Science Foundation of China,No.82000579Qinghai Provincial Health System Key Project No.2021-wjzd-06Foundation Research Project of Qinghai Province,2023-ZJ-786.
文摘Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.Methods:After observing epithelial-mesenchymal transformation(EMT)changes in HepG2 and HepG2/Sorafenib cells,we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC.Subsequently,specific inhibitors of c-Jun N-terminal kinase(JNK,SP600125)and extracellular signal-regulated kinase(ERK,PD98059)were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor(EGFR)/JNK/ERK signaling pathway in vitro and in vivo.Biological behavior changes were assessed through cell counting kit-8(CCK-8),colony formation,transwell,and immunofluorescence tests.Simultaneously,Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.Results:The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells,and sorafenib-resistant HCC was characterized by EMT changes.Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells,with minimal impact on HepG2 cells.Additionally,apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells.Furthermore,there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups.Notably,SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.Conclusion:Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.
文摘BACKGROUND Patients with liver cancer complicated by portal hypertension present complex challenges in treatment.AIM To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this condition.METHODS Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group(n=50)and a control group(n=50)according to the treatment regimen.The research group received radiofrequency ablation(RFA)in combination with sorafenib,and the control group only received RFA.The short-term efficacy of both the research and control groups was observed.Liver function and portal hypertension were compared before and after treatment.Alpha-fetoprotein(AFP),glypican-3(GPC-3),and AFP-L3 levels were compared between the two groups prior to and after treatment.The occurrence of adverse reactions in both groups was observed.The 3-year survival rate was compared between the two groups.Basic data were compared between the survival and non-surviving groups.To identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension,multivariate logistic regression analysis was employed.RESULTS When comparing the two groups,the research group's total effective rate(82.00%)was significantly greater than that of the control group(56.00%;P<0.05).Following treatment,alanine aminotransferase and aspartate aminotransferase levels increased,and portal vein pressure decreased in both groups.The degree of improvement for every index was substantially greater in the research group than in the control group(P<0.05).Following treatment,the AFP,GPC-3,and AFP-L3 levels in both groups decreased,with the research group having significantly lower levels than the control group(P<0.05).The incidence of diarrhea,rash,nausea and vomiting,and fatigue in the research group was significantly greater than that in the control group(P<0.05).The 1-,2-,and 3-year survival rates of the research group(94.00%,84.00%,and 72.00%,respectively)were significantly greater than those of the control group(80.00%,64.00%,and 40.00%,respectively;P<0.05).Significant differences were observed between the survival group and the non-surviving group in terms of Child-Pugh grade,history of hepatitis,number of tumors,tumor size,use of sorafenib,stage of liver cancer,histological differentiation,history of splenectomy and other basic data(P<0.05).Logistic regression analysis demonstrated that high Child-Pugh grade,tumor size(6–10 cm),history of hepatitis,no use of sorafenib,liver cancer stage IIIC,and previous splenectomy were independent risk factors for poor prognosis in patients with liver cancer complicated with portal hypertension(P<0.05).CONCLUSION Patients suffering from liver cancer complicated by portal hypertension benefit from the combination of RFA and sorafenib therapy because it effectively restores liver function and increases survival rates.The prognosis of patients suffering from liver cancer complicated by portal hypertension is strongly associated with factors such as high Child-Pugh grade,tumor size(6-10 cm),history of hepatitis,lack of sorafenib use,liver cancer at stage IIIC,and prior splenectomy.
基金supported by Startup Fund for Scientific Research,Fujian Medical University(No.2019QH1146)Guiyang Science and The Natural Science Foundation of Fujian Province(general program)(No.2020J011061).
文摘Objective Mitofusin-2(MFN2)is a mitochondrial membrane protein that plays a critical role in regulating mitochondrial fusion and cellular metabolism.To further elucidate the impact of MFN2,this study aimed to investigate its significance on hepatocellular carcinoma(HCC)cell function and its potential role in mediating chemosensitivity.Methods This study investigated the effects of silencing and overexpressing MFN2 on the survival,proliferation,invasion and migration abilities,and sorafenib resistance of MHCC97-L HCC cells.Additional experiments were conducted using XAV939(aβ-catenin inhibitor)and HLY78(aβ-catenin activator)to further validate these findings.Results Silencing MFN2 significantly promoted the survival and proliferation of MHCC97-L cells,enhanced their invasion and migration capacities,increased the IC50 of sorafenib,reduced the percentage of TUNEL-positive cells,and decreased the expression of proapoptotic proteins.Additionally,silencing MFN2 markedly induced the nuclear translocation ofβ-catenin,increasedβ-catenin acetylation levels and enhanced the expression of the downstream regulatory proteins Snail1 and Vimentin while inhibiting E-cadherin expression.Conversely,overexpressing MFN2 reversed the effects observed in MHCC97-L cells mentioned above.The results confirmed that silencing MFN2 activated theβ-catenin/epithelial-mesenchymal transition(EMT)pathway and reduced the sensitivity of cells to sorafenib,which could be reversed by XAV939 treatment.Conversely,overexpression of MFN2 inhibited theβ-catenin/EMT pathway and increased the sensitivity of cells to sorafenib,which could be altered by HLY78.Conclusion Low expression of MFN2 in HCC cells promotes the nuclear translocation ofβ-catenin,thereby activating the EMT pathway and mediating resistance to sorafenib.
基金Supported by the National Natural Science Foundation of China,No.82271628.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a prevalent and aggressive tumor.Sorafenib is the first-line treatment for patients with advanced HCC,but resistance to sorafenib has become a significant challenge in this therapy.Cancer stem cells play a crucial role in sorafenib resistance in HCC.Our previous study revealed that the long non-coding RNA(lncRNA)KIF9-AS1 is an oncogenic gene in HCC.However,the role of KIF9-AS1 in drug resistance and cancer stemness in HCC remains unclear.Herein,we aimed to investigate the function and mechanism of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC.AIM To describe the role of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC and elucidate the underlying mechanism.METHODS Tumor tissue and adjacent non-cancerous tissue samples were collected from HCC patients.Sphere formation was quantified via a tumor sphere assay.Cell viability,proliferation,and apoptosis were evaluated via Cell Counting Kit-8,flow cytometry,and colony formation assays,respectively.The interactions between the lncRNA KIF9-AS1 and its downstream targets were confirmed via RNA immunoprecipitation and coimmunoprecipitation.The tumorigenic role of KIF9-AS1 was validated in a mouse model.RESULTS Compared with that in normal controls,the expression of the lncRNA KIF9-AS1 was upregulated in HCC tissues.Knockdown of KIF9-AS1 inhibited stemness and attenuated sorafenib resistance in HCC cells.Mechanistically,N6-methyladenosine modification mediated by methyltransferase-like 3/insulin-like growth factor 2 mRNA-binding protein 1 stabilized and increased the expression of KIF9-AS1.Additionally,KIF9-AS1 increased the stability and expression of short stature homeobox 2 by promoting ubiquitin-specific peptidase 1-induced deubiquitination.Furthermore,depletion of KIF9-AS1 alleviated sorafenib resistance in a xenograft mouse model of HCC.CONCLUSION The N6-methyladenosine-modified lncRNA KIF9-AS1 promoted stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expression.
基金The present study was supported by the Sichuan Science and Technology Program(2023YFG0262).
文摘Hepatocellular carcinoma(HCC)poses a significant threat to human health.Resistance to sorafenib in the chemotherapy of HCC is a common and significant issue that profoundly impacts clinical treatment.While several members of the transmembrane(TMEM)protein family have been implicated in the occurrence and progression of HCC,the association between TMEM39b and HCC remains unexplored.This study revealed a significant overexpression of TMEM39b in HCC,which correlated with a poor prognosis.Subsequent investigation revealed that RAS-selective lethal 3(RSL3)induced pronounced ferroptosis in HCC,and knocking down the expression of TMEM39b significantly decreased its severity.Similarly,following the induction of ferroptosis in HCC by sorafenib,knocking down the expression of TMEM39b also decreased the severity of ferroptosis,enhancing HCC tolerance to sorafenib.In conclusion,we propose that TMEM39b promotes tumor progression and resistance to sorafenib by inhibiting ferroptosis in HCC.
基金supported by the open fund of State Key Laboratory of Southwestern Chinese Medicine Resources(No.SCMR202103)to Jian LiTibet Autonomous Region Science and Technology Plan(high-tech social development)project(No.XZ202201ZY0031G)to Yi-Xi YangAnti-infective Agent Creation Engineering Research Centre of Sichuan Province,Sichuan Industrial Institute of Antibiotics,School of pharmacy,Chengdu University(No.AAC2023002)to Qiu-Xia Lu.
文摘Background:Drug-induced liver damage is a severe medical issue that affects people all over the world.Sorafenib has some side effects that cause liver injury.A dietary medicinal plant called Penthorum chinense Pursh.(PCP)has hepatoprotective properties.There are currently few reports on PCP’s protective impact and mechanism against sorafenib-induced liver injury.Methods:To create a liver injury model,sorafenib was administered to BRL-3A cells.Cell viability assays,immunofluorescence tests,Western blotting,real-time quantitative PCR,and high-content imaging systems were utilized to examine PCP’s effect and mechanism.Results:In this study,PCP treatment mitigated the liver damage caused by sorafenib by enhancing cell survival,lowering lipid reactive oxygen species and malondialdehyde levels,and elevating glutathione levels.In addition,PCP can enhance the protein expression of cystine/glutamate transporter xCT and glutathione peroxidase 4,reduce iron content and alleviate mitochondrial toxicity.Further mechanism studies revealed that PCP inhibited ferroptosis by promoting the production of nuclear factor E2-related factor 2 nuclear translocation and subsequently affecting target genes(HO-1 and NQO1).Conclusion:Together,PCP regulates the nuclear factor E2-related factor 2 pathway,which helps to lessen ferroptosis brought on by sorafenib.
基金supported by the open fund of State Key Laboratory of Southwestern Chinese Medicine Resources(No.SCMR202103)to Jian LiTibet Autonomous Region Science and Technology Plan(high-tech social development)project(No.XZ202201ZY0031G)to Yang YXAnti-infective Agent Creation Engineering Research Centre of Sichuan Province,Sichuan Industrial Institute of Antibiotics,School of pharmacy,Chengdu University(No.AAC2023002)to Lu QX.
文摘Background:Luteolin is a flavonoid chemical that exists in a variety of medicinal and edible plants and holds many biologically active properties in liver protection,anti-cancer,antioxidants,anti-inflammatory,neuroprotective,etc.According to its hepatoprotective properties,luteolin was selected to co-treat with sorafenib,one of the approved protein kinase inhibitors,to reduce sorafenib-induced normal liver cell damage.Methods:The BRL-3A cell line was treated with sorafenib to establish a liver injury model,followed by luteolin treatment.The cell viability was detected,and the mechanism of action was detected by immunofluorescence,western blotting,and real-time quantitative PCR.Results:The research findings demonstrated that luteolin could increase cystine/glutamate transporter xCT(SLC7A11)and glutathione peroxidase 4(GPX4)expression and display a chelating effect on iron,which led to increased glutathione and decreased malondialdehyde,Fe^(2+) and lipid reactive oxygen species contents in BRL-3A cells,and the sorafenib-induced mitochondrial membrane potential decrease was also inhibited.In addition,when sorafenib caused the accumulation of lipid reactive oxygen species,luteolin could help release this oxidative stress by activating nuclear factor E2-related factor 2(Nrf2)and up-regulating the expression of the associated genes heme oxygenase 1(HO-1)and quinone oxidoreductase 1(NQO1).Conclusion:Therefore,luteolin may ameliorate sorafenib-induced ferroptosis by activating the Nrf2-associated pathway without any impact on sorafenib anti-cancer activity.It can be used as an adjuvant to sorafenib to reduce liver injury in patients with hepatocellular carcinoma.
基金Supported by Sichuan Science and Technology Project,No.2021YJ0138Research Subject of Sichuan Provincial Health Commission,No.19PJ007Chengdu Science and Technology Project,No.2021-YF05-01788-SN.
文摘BACKGROUND Although the past decade has seen remarkable advances in treatment options for hepatocellular carcinoma(HCC),the dismal overall prognosis still envelops HCC patients.Several comparative trials have been conducted to study whether transarterial chemoembolization(TACE)could improve clinical outcomes in patients receiving sorafenib for advanced HCC;however,the findings have been inconsistent.AIM To study the potential synergies and safety of sorafenib plus TACE vs sorafenib alone for treating advanced HCC,by performing a systematic review and metaanalysis.METHODS This study was conducted following the PRISMA statement.A systematic literature search was conducted using the Cochrane Library,Embase,PubMed,and Web of Science databases.Data included in the present work were collected from patients diagnosed with advanced HCC receiving sorafenib plus TACE or sorafenib alone.Data synthesis and meta-analysis were conducted using Review Manager software.RESULTS The present study included 2780 patients from five comparative clinical trials(1 was randomized control trial and 4 were retrospective studies).It was found that patients receiving sorafenib plus TACE had better prognoses in terms of overall survival(OS),with a combined hazard ratio(HR)of 0.65[95%confidence interval(95%CI):0.46–0.93,P=0.02,n=2780].Consistently,progression free survival(PFS)and time to progression(TTP)differed significantly between the sorafenib plus TACE arm and sorafenib arm(PFS:HR=0.62,95%CI:0.40–0.96,P=0.03,n=443;TTP:HR=0.73,95%CI:0.64-0.83,P<0.00001,n=2451).Disease control rate(DCR)was also significantly increased by combination therapy(risk ratio=1.36,95%CI:1.02-1.81,P=0.04,n=641).Regarding safety,the incidence of any adverse event(AE)was increased due to the addition of TACE;however,no significant difference was found in grade≥3 AEs.CONCLUSION The combination of sorafenib with TACE has superior efficacy to sorafenib monotherapy,as evidenced by prolonged OS,PFS,and TTP,as well as increased DCR.Additional high-quality trials are essential to further validate the clinical benefit of this combination in the treatment of advanced HCC.
文摘Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. The delivery of therapeutic compounds to the target site is a major challenge in the treatment of many diseases. Objective: This study aims to evaluate activated charcoal nanoparticles as a drug delivery system for anticancer agents (Sorafenib and Doxorubicin) in Hepatocellular Cancer Stem Cells. Method: The percent efficiency of entrapment (% EE) of the doxorubicin and sorafenib entrapped onto the activated charcoal was obtained by determining the free doxorubicin and sorafenib concentration in the supernatant-prepared solutions. Then the characterizations of nanoparticles were formed by determination of the particle size distribution, zeta potential, and polydispersity index (PDI). The anticancer activity of activated Charcoal, Doxorubicin-ACNP, sorafenib-ACNP, free doxorubicin, and free sorafenib solutions was measured based on cell viability percentage in HepG2 cell lines (ATCC-CCL 75). In vitro RBC’s toxicity of Doxorubicin/sorafenib loaded charcoal was estimated by hemolysis percentage. Results: The synthesized Doxorubicin-ACNP and Sorafenib-ACNP were evaluated and their physiochemical properties were also examined. Essentially, the percent Efficiency of Entrapment (EE %) was found to be 87.5% and 82.66% for Doxorubicin-ACNP and Sorafenib-ACNP, respectively. The loading capacity was 34.78% and 24.31% for Doxorubicin-ACNP and Sorafenib-ACNP. Using the Dynamic Light scattering [DLS] for the determination of the hydrodynamic size and surface zeta potential, a narrow sample size distribution was obtained of (18, 68, and 190 nm for charcoal, 105, 255, and 712 nm for doxorubicin, and 91, 295, and 955 nm for sorafenib), respectively. A surface charge of −13.2, −15.6 and −17 was obtained for charcoal, doxorubicin/charcoal, and sorafenib/charcoal nanoparticles. The cytotoxic activity of Doxorubicin-ACNP and Sorafenib-ACNP was evaluated in-vitro against HepG2 cell lines and it was observed that Drug loaded ACNP improved anticancer activity when compared to Doxorubicin or Sorafenib alone. Moreover, testing the toxicity potential of DOX-ACNP and Sorafenib-ACNP showed a significant reduction in the hemolysis of red blood cells when compared to Doxorubicin and Sorafenib alone. Conclusion: In conclusion, it is notable to state that this study is regarded as the first to investigate the use of Activated charcoal for the loading of Doxorubicin and Sorafenib for further use in the arena of hepatocellular carcinoma. Doxorubicin-ACNP and Sorafenib-ACNP showed noteworthy anticancer activity along with a reduced potential of RBCs hemolysis rendering it as an efficacious carrier with a low toxicity potential.
基金Supported by Henan Province Medical Science and Technology Tackling Program Joint Co-Construction Project,No.LHGJ20191024。
文摘BACKGROUND In the quest to manage hepatocellular carcinoma(HCC),the focus has shifted to a more holistic approach encompassing both data analytics and innovative treatments.Analyzing rich data resources,such as the cancer genome atlas(TCGA),and examining progressive therapies can potentially reshape the trajectory of HCC treatment.AIM To elucidate the immunological genes and the underlying mechanism of the combined Kombo knife and sorafenib regimen for HCC by analyzing data from TCGA and machine learning data.METHODS Immune attributes were evaluated via TCGA's postablation HCC RNA sequencing data.Using weighted gene coexpression network analysis and machine learning,we identified genes with high prognostic value.The therapeutic landscape and safety metrics of the integrated treatment were critically evaluated across cellular and animal models.RESULTS Immune genes–specifically,peptidylprolyl isomerase A and solute carrier family 29 member 3–emerged as significant prognostic markers.Enhanced therapeutic outcomes,such as prolonged progression-free survival and an elevated overall response rate,characterize the combined approach,with peripheral blood mononuclear cells displaying potent effects on HCC dynamics.CONCLUSION The combination of Kombo knife with sorafenib is an innovative HCC treatment modality anchored in immunecentric strategies.
