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 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
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
Objective:To investigate the role and mechanism of mTOR in sorafenib-ameliorated liver fibrosis by inducing hepatic stellate cells(HSC)ferroptosis.Methods:The liver fibrosis models of C57BL/6 male mice were induced wi...Objective:To investigate the role and mechanism of mTOR in sorafenib-ameliorated liver fibrosis by inducing hepatic stellate cells(HSC)ferroptosis.Methods:The liver fibrosis models of C57BL/6 male mice were induced with carbon tetrachloride(CCl4)and randomly divided into normal group,model group,and sorafenib low(2.5 mg/kg),medium(5 mg/kg),and high(10 mg/kg)dose groups.Except for the normal group,the remaining four groups were treated with intraperitoneal injection of CCl4 for 8 weeks to establish liver fibrosis models.In addition,the corresponding concentrations of sorafenib were administered during the fourth week of modeling.Western blot was used to detect the expression of mTOR and p-mTOR protein in liver tissues.In vitro experiments,HSC-T6 cells were activated by PDGFBB and then treated with sorafenib(5μM,10μM,20μM),an mTOR inhibitor and activator.CCK8 was used to detect HSC-T6 cell viability,Western blot detected the protein expression ofα-SMA,COL1α1,GPX4,mTOR and p-mTOR.The levels of serum iron,GSH,and MDA were measured,and the intracellular ROS level was measured by 2',7'-dichlorofluorescein diacetate and dihydroethidium.Results:In vitro results showed that sorafenib significantly decreased the protein expression ofα-SMA,COL1α1,GPX4 and p-mTOR,and decreased the level of GSH and increased the content of iron,MDA and ROS in HSC-T6(P<0.05).Sorafenib(5μM,10μM,20μM)significantly inhibited the cell viability of PDGF-BB-enhanced HSCT6(P<0.05).When mTOR was inhibited,the protein expressions ofα-SMA,COL1α1 and GPX4 and the level of GSH were lower(P<0.05),and the contents of iron,MDA and ROS were further increased(P<0.05).When mTOR was activated,the results were reversed.Conclusion:Sorafenib induced ferroptosis to alleviate liver fibrosis,and inhibition of mTOR further enhanced the effect of sorafenib.展开更多
BACKGROUND Resistance to sorafenib has become a challenge in clinical treatment of hepatocellular carcinoma(HCC).Physcion is a common bioactive anthraquinone that has potential as an anticancer agent.AIM To study the ...BACKGROUND Resistance to sorafenib has become a challenge in clinical treatment of hepatocellular carcinoma(HCC).Physcion is a common bioactive anthraquinone that has potential as an anticancer agent.AIM To study the effect of physcion on sensitizing HCC cells to sorafenib.METHODS Sorafenib-resistant HCC cells were established and treated with sorafenib and/or physcion.The cell viability,proliferation and apoptosis were measured by cell counting kit-8,colony formation,flow cytometry,and in vivo xenograft model.Glucose uptake,lactate acid production,extracellular acidification rate(ECAR),and oxygen consumption rate(OCR)were measured to analyze glycolysis.Expression of glycolysis-related regulators was assessed by western blotting.RESULTS The addition of physcion significantly enhanced the antitumor effects of sorafenib on sorafenib-resistant HCC cells,manifested by enhanced apoptosis and suppressed cell growth.The glucose uptake,lactate acid production,and ECAR were elevated,and OCR was suppressed by physcion treatment.The level of PIM1 was elevated and miR-370 was suppressed in sorafenib-resistant HCC cells compared with the parental cells,which was suppressed by physcion treatment.Inhibition of miR-370 notably reversed the effects of physcion on sorafenib-resistant HCC cells.CONCLUSION Our data indicated that physcion enhanced the sensitivity of HCC cells to sorafenib by enhancing miR-370 to suppress PIM1-promoted glycolysis.展开更多
BACKGROUND In the United States,sorafenib monotherapy was approved in 2007 for first-line(1L)treatment of patients with unresectable hepatocellular carcinoma(uHCC).As other therapies have been approved in recent years...BACKGROUND In the United States,sorafenib monotherapy was approved in 2007 for first-line(1L)treatment of patients with unresectable hepatocellular carcinoma(uHCC).As other therapies have been approved in recent years for hepatocellular carcinoma treatment in later lines,it is essential to assess clinical effectiveness of older therapies in actual clinical practice to inform healthcare practitioners’decisions for better patient care.AIM To assess patient characteristics/clinical effectiveness of 1L sorafenib in uHCC patients treated in United States academic and community practice settings.METHODS A retrospective observational study was conducted among adult patients(≥18 years)in the United States initiating sorafenib monotherapy as 1L systemic therapy for uHCC with Eastern Cooperative Oncology Group status of 0 or 1 between January 2016 and December 2019 at City of Hope and Advent Health.Data were extracted by trained abstractionists from individual patients’electronic health records and captured in electronic case report forms.Institutional Review Board approvals were obtained prior to study initiation.Data were captured from the time of sorafenib initiation until death or the end of follow-up.All data were de-identified prior to analyses.Clinical outcomes assessed included provider-reported best response,progression-free survival(PFS),and overall survival(OS).PFS and OS were estimated using Kaplan-Meier methods.RESULTS Among 134 uHCC patients treated with 1L sorafenib,majority were male(75%),and most were Caucasian(62%)or Asian(19%).Median patient age was 64 years.The most common etiologies of liver disease were hepatitis C(54%),alcohol-related liver disease(16%),and hepatitis B(11%).Most patients were reported to have Barcelona Clinic Liver Cancer stage B(19%)or stage C(70%)disease.Of 134 patients,110(82%)were reported to have discontinued treatment or died during follow-up.Primary reasons for sorafenib discontinuation were reported as progression(35%)and toxicity(30%).Best overall response was reported for 124 patients,of which 7.3%reported complete or partial response.Median time to treatment discontinuation was 2.3 mo.Overall,103 patients(77%)had disease progression or died during sorafenib therapy.Median PFS was estimated to be 2.9 mo.At the end of follow-up,82 patients(61%)were deceased.Median OS was 8.5 mo.CONCLUSION Newer therapeutic options that have reported higher PFS and OS in real-world clinical practice should be considered to enhance patient outcomes.展开更多
Objective:To investigate the effects and possible mechanisms of the combination of DMDD(2-dodecyl-6-methoxycyclohexa-2-5-diene-1-4-dione),a traditional Chinese medicine monomer,and sorafenib on the malignant biologica...Objective:To investigate the effects and possible mechanisms of the combination of DMDD(2-dodecyl-6-methoxycyclohexa-2-5-diene-1-4-dione),a traditional Chinese medicine monomer,and sorafenib on the malignant biological behavior of human hepatocellular carcinoma Huh7 cells.Methods:The experiment was divided into four groups:Huh7 cells control group,DMDD group,sorafenib group and DMDD and sorafenib combination group.The CCK-8 assay was used to measure the viability of Huh7 cells,and the Kim's formula was used to determine the synergistic effect.The plate cloning experiment was conducted to test colony formation ability of Huh7 cells.The scratch and Transwell experiments were performed to evaluate the migration ability and the invasion ability of Huh7 cells.The cell cycle of Huh7 cells was detected by flow cytometry.RT-qPCR and Western blot were used to measure the mRNA transcription level and protein expression level of PHGDH in the serine synthesis pathway.Results:The plate cloning experiment,scratch experiment,and Transwell migration experiment showed that the combined application of DMDD and Sorafenib significantly enhanced the inhibitory effect on the proliferation,migration,and invasion ability of Huh7 cells compared to the control group,DMDD group,and Sorafenib group(P<0.05).According to the Kim's formula,the combination of DMDD(final concentrations of 2,4,8μmol/L)and Sorafenib(final concentrations of 1,2,4μmol/L)had a synergistic inhibitory effect on the proliferation of Huh7 cells(Q>1.15).6,10μmol/L DMDD combined with 3,5μmol/L Sorafenib showed additive effect.The cell cycle of Huh7 cells was detected by flow cytometry,and the results showed that after 48 hours of drug intervention,the proportion of G2/M phase cells in the control group,DMDD group,Sorafenib group,and combination group were(10.63±0.32)%,(35.77±1.22)%,(30.03±2.22)%,and(38.97±0.60)%,respectively.Compared with the control group,the proportion of G2/M phase cells in the three groups significantly increased(P<0.0001).Compared with the Sorafenib group,the proportion of G2/M phase cells in the combination group significantly increased(P<0.0001).RT-qPCR and Western blot results showed that the combined application of DMDD and Sorafenib significantly inhibited the mRNA transcription level and protein expression level of PHGDH(P<0.05).Conclusion:The combined application of DMDD and Sorafenib has a synergistic effect that can enhance the inhibitory effect on the proliferation,invasion,and migration ability of Huh7 cells.The mechanism of this effect is related to the synergistic inhibition of the gene transcription and protein expression of PHGDH in the serine synthesis pathway.展开更多
Objective:To investigate the mechanism of long non-coding RNA-LINC00662 on induction of sorafenib resistance in hepatocellular carcinoma(HCC)cells.Methods:HCC cells(HepG2,HCCLM3),sorafenib-resistant hepatocellular car...Objective:To investigate the mechanism of long non-coding RNA-LINC00662 on induction of sorafenib resistance in hepatocellular carcinoma(HCC)cells.Methods:HCC cells(HepG2,HCCLM3),sorafenib-resistant hepatocellular carcinoma cells HCC-SR(HepG2-SR,HCCLM3-SR)were investigated by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR)and Western blot was used to detect LINC00662,miR-106a-5p and cavitin-1(CAV1)expression in each group of cells.106a-5p and cavitin-1(CAV1)expression levels were measured by RT-qPCR and Western blot.The si-LINC00662 and miR-106a-5p mimics were transfected with HCC-SR cells,respectively,and cell sensitivity to sorafenib drug was detected by cell activity kit(CCK-8).And the targeting relationship between LINC00662 and miR-106a-5p,miR-106a-5p and CAV1 was further determined by dual luciferase reporter assay,RT-qPCR,and Western blot.Results:The relative expression of LINC00662 and CAV1 was significantly increased and miR-106a-5p expression was significantly decreased in HCC-SR cells(P<0.01,P<0.001);interference with LINC00662 expression or overexpression of miR-106a-5p significantly increased the sensitivity of HCC-SR cells to sorafenib drug(P<0.05,P<0.01).And LINC00662 targeted to negatively regulate miR-106a-5p expression and miR-106a-5p targeted to negatively regulate CAV1 expression(P<0.05).Conclusion:LINC00662 could act as a competitive endogenous RNA(ceRNA)of miR-106a-5p to promote the expression of CAV1 and mediate the resistance of sorafenib in HCC cells.Interfering with LINC00662 expression can inhibit sorafenib resistance and increase sorafenib drug sensitivity in HCC cells.展开更多
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.
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Foundation Project of National Natural Science(81600498)。
文摘Objective:To investigate the role and mechanism of mTOR in sorafenib-ameliorated liver fibrosis by inducing hepatic stellate cells(HSC)ferroptosis.Methods:The liver fibrosis models of C57BL/6 male mice were induced with carbon tetrachloride(CCl4)and randomly divided into normal group,model group,and sorafenib low(2.5 mg/kg),medium(5 mg/kg),and high(10 mg/kg)dose groups.Except for the normal group,the remaining four groups were treated with intraperitoneal injection of CCl4 for 8 weeks to establish liver fibrosis models.In addition,the corresponding concentrations of sorafenib were administered during the fourth week of modeling.Western blot was used to detect the expression of mTOR and p-mTOR protein in liver tissues.In vitro experiments,HSC-T6 cells were activated by PDGFBB and then treated with sorafenib(5μM,10μM,20μM),an mTOR inhibitor and activator.CCK8 was used to detect HSC-T6 cell viability,Western blot detected the protein expression ofα-SMA,COL1α1,GPX4,mTOR and p-mTOR.The levels of serum iron,GSH,and MDA were measured,and the intracellular ROS level was measured by 2',7'-dichlorofluorescein diacetate and dihydroethidium.Results:In vitro results showed that sorafenib significantly decreased the protein expression ofα-SMA,COL1α1,GPX4 and p-mTOR,and decreased the level of GSH and increased the content of iron,MDA and ROS in HSC-T6(P<0.05).Sorafenib(5μM,10μM,20μM)significantly inhibited the cell viability of PDGF-BB-enhanced HSCT6(P<0.05).When mTOR was inhibited,the protein expressions ofα-SMA,COL1α1 and GPX4 and the level of GSH were lower(P<0.05),and the contents of iron,MDA and ROS were further increased(P<0.05).When mTOR was activated,the results were reversed.Conclusion:Sorafenib induced ferroptosis to alleviate liver fibrosis,and inhibition of mTOR further enhanced the effect of sorafenib.
基金Supported by National Natural Science Foundation of China,No.81960782.
文摘BACKGROUND Resistance to sorafenib has become a challenge in clinical treatment of hepatocellular carcinoma(HCC).Physcion is a common bioactive anthraquinone that has potential as an anticancer agent.AIM To study the effect of physcion on sensitizing HCC cells to sorafenib.METHODS Sorafenib-resistant HCC cells were established and treated with sorafenib and/or physcion.The cell viability,proliferation and apoptosis were measured by cell counting kit-8,colony formation,flow cytometry,and in vivo xenograft model.Glucose uptake,lactate acid production,extracellular acidification rate(ECAR),and oxygen consumption rate(OCR)were measured to analyze glycolysis.Expression of glycolysis-related regulators was assessed by western blotting.RESULTS The addition of physcion significantly enhanced the antitumor effects of sorafenib on sorafenib-resistant HCC cells,manifested by enhanced apoptosis and suppressed cell growth.The glucose uptake,lactate acid production,and ECAR were elevated,and OCR was suppressed by physcion treatment.The level of PIM1 was elevated and miR-370 was suppressed in sorafenib-resistant HCC cells compared with the parental cells,which was suppressed by physcion treatment.Inhibition of miR-370 notably reversed the effects of physcion on sorafenib-resistant HCC cells.CONCLUSION Our data indicated that physcion enhanced the sensitivity of HCC cells to sorafenib by enhancing miR-370 to suppress PIM1-promoted glycolysis.
文摘BACKGROUND In the United States,sorafenib monotherapy was approved in 2007 for first-line(1L)treatment of patients with unresectable hepatocellular carcinoma(uHCC).As other therapies have been approved in recent years for hepatocellular carcinoma treatment in later lines,it is essential to assess clinical effectiveness of older therapies in actual clinical practice to inform healthcare practitioners’decisions for better patient care.AIM To assess patient characteristics/clinical effectiveness of 1L sorafenib in uHCC patients treated in United States academic and community practice settings.METHODS A retrospective observational study was conducted among adult patients(≥18 years)in the United States initiating sorafenib monotherapy as 1L systemic therapy for uHCC with Eastern Cooperative Oncology Group status of 0 or 1 between January 2016 and December 2019 at City of Hope and Advent Health.Data were extracted by trained abstractionists from individual patients’electronic health records and captured in electronic case report forms.Institutional Review Board approvals were obtained prior to study initiation.Data were captured from the time of sorafenib initiation until death or the end of follow-up.All data were de-identified prior to analyses.Clinical outcomes assessed included provider-reported best response,progression-free survival(PFS),and overall survival(OS).PFS and OS were estimated using Kaplan-Meier methods.RESULTS Among 134 uHCC patients treated with 1L sorafenib,majority were male(75%),and most were Caucasian(62%)or Asian(19%).Median patient age was 64 years.The most common etiologies of liver disease were hepatitis C(54%),alcohol-related liver disease(16%),and hepatitis B(11%).Most patients were reported to have Barcelona Clinic Liver Cancer stage B(19%)or stage C(70%)disease.Of 134 patients,110(82%)were reported to have discontinued treatment or died during follow-up.Primary reasons for sorafenib discontinuation were reported as progression(35%)and toxicity(30%).Best overall response was reported for 124 patients,of which 7.3%reported complete or partial response.Median time to treatment discontinuation was 2.3 mo.Overall,103 patients(77%)had disease progression or died during sorafenib therapy.Median PFS was estimated to be 2.9 mo.At the end of follow-up,82 patients(61%)were deceased.Median OS was 8.5 mo.CONCLUSION Newer therapeutic options that have reported higher PFS and OS in real-world clinical practice should be considered to enhance patient outcomes.
基金This study was supported by National Natural Foundation Project of China(81860504)。
文摘Objective:To investigate the effects and possible mechanisms of the combination of DMDD(2-dodecyl-6-methoxycyclohexa-2-5-diene-1-4-dione),a traditional Chinese medicine monomer,and sorafenib on the malignant biological behavior of human hepatocellular carcinoma Huh7 cells.Methods:The experiment was divided into four groups:Huh7 cells control group,DMDD group,sorafenib group and DMDD and sorafenib combination group.The CCK-8 assay was used to measure the viability of Huh7 cells,and the Kim's formula was used to determine the synergistic effect.The plate cloning experiment was conducted to test colony formation ability of Huh7 cells.The scratch and Transwell experiments were performed to evaluate the migration ability and the invasion ability of Huh7 cells.The cell cycle of Huh7 cells was detected by flow cytometry.RT-qPCR and Western blot were used to measure the mRNA transcription level and protein expression level of PHGDH in the serine synthesis pathway.Results:The plate cloning experiment,scratch experiment,and Transwell migration experiment showed that the combined application of DMDD and Sorafenib significantly enhanced the inhibitory effect on the proliferation,migration,and invasion ability of Huh7 cells compared to the control group,DMDD group,and Sorafenib group(P<0.05).According to the Kim's formula,the combination of DMDD(final concentrations of 2,4,8μmol/L)and Sorafenib(final concentrations of 1,2,4μmol/L)had a synergistic inhibitory effect on the proliferation of Huh7 cells(Q>1.15).6,10μmol/L DMDD combined with 3,5μmol/L Sorafenib showed additive effect.The cell cycle of Huh7 cells was detected by flow cytometry,and the results showed that after 48 hours of drug intervention,the proportion of G2/M phase cells in the control group,DMDD group,Sorafenib group,and combination group were(10.63±0.32)%,(35.77±1.22)%,(30.03±2.22)%,and(38.97±0.60)%,respectively.Compared with the control group,the proportion of G2/M phase cells in the three groups significantly increased(P<0.0001).Compared with the Sorafenib group,the proportion of G2/M phase cells in the combination group significantly increased(P<0.0001).RT-qPCR and Western blot results showed that the combined application of DMDD and Sorafenib significantly inhibited the mRNA transcription level and protein expression level of PHGDH(P<0.05).Conclusion:The combined application of DMDD and Sorafenib has a synergistic effect that can enhance the inhibitory effect on the proliferation,invasion,and migration ability of Huh7 cells.The mechanism of this effect is related to the synergistic inhibition of the gene transcription and protein expression of PHGDH in the serine synthesis pathway.
基金This study was supported by National Natural Science Foundation of China(No.81360359)2021 Innovation and Entrepreneurship Training Program for University Students,Hainan Medical University(No.202111810003)。
文摘Objective:To investigate the mechanism of long non-coding RNA-LINC00662 on induction of sorafenib resistance in hepatocellular carcinoma(HCC)cells.Methods:HCC cells(HepG2,HCCLM3),sorafenib-resistant hepatocellular carcinoma cells HCC-SR(HepG2-SR,HCCLM3-SR)were investigated by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR)and Western blot was used to detect LINC00662,miR-106a-5p and cavitin-1(CAV1)expression in each group of cells.106a-5p and cavitin-1(CAV1)expression levels were measured by RT-qPCR and Western blot.The si-LINC00662 and miR-106a-5p mimics were transfected with HCC-SR cells,respectively,and cell sensitivity to sorafenib drug was detected by cell activity kit(CCK-8).And the targeting relationship between LINC00662 and miR-106a-5p,miR-106a-5p and CAV1 was further determined by dual luciferase reporter assay,RT-qPCR,and Western blot.Results:The relative expression of LINC00662 and CAV1 was significantly increased and miR-106a-5p expression was significantly decreased in HCC-SR cells(P<0.01,P<0.001);interference with LINC00662 expression or overexpression of miR-106a-5p significantly increased the sensitivity of HCC-SR cells to sorafenib drug(P<0.05,P<0.01).And LINC00662 targeted to negatively regulate miR-106a-5p expression and miR-106a-5p targeted to negatively regulate CAV1 expression(P<0.05).Conclusion:LINC00662 could act as a competitive endogenous RNA(ceRNA)of miR-106a-5p to promote the expression of CAV1 and mediate the resistance of sorafenib in HCC cells.Interfering with LINC00662 expression can inhibit sorafenib resistance and increase sorafenib drug sensitivity in HCC cells.