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STIM1 promotes acquired resistance to sorafenib by attenuating ferroptosis in hepatocellular carcinoma
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作者 Ran Ren Yu Chen +9 位作者 Yu Zhou Luyao Shen Yang Chen Juan Lei Jingchun Wang Xudong Liu Nan Zhang Dongqin Zhou Huakan Zhao Yongsheng Li 《Genes & Diseases》 SCIE CSCD 2024年第6期466-481,共16页
Dysregulated calcium(Ca?+)signaling pathways are associated with tumor cell death and drug resistance.In non-excitable cells,such as hepatocellular carcinoma(HcC)cells,the primary pathway for Ca2+influx is through str... Dysregulated calcium(Ca?+)signaling pathways are associated with tumor cell death and drug resistance.In non-excitable cells,such as hepatocellular carcinoma(HcC)cells,the primary pathway for Ca2+influx is through stromal interaction molecule 1(STIM1)-mediated store-operated calcium entry(SOCE).Previous studies have demonstrated the involvement of STIM1-mediated SOCE in processes such as genesis,metastasis,and stem cell self-renewal of HCC.However,it remains unclear whether STIM1-mediated SOCE plays a role in developing acquired resistance to sorafenib in HcC patients.In this study,we established acquired sorafenib-resistant(SR)HCC cell lines by intermittently exposing them to increasing concentrations of sorafenib.Our results showed higher levels of STIM1 and stronger SOCE in SR cells compared with parental cells.Deleting STIM1 significantly enhanced sensitivity to sorafe-nib in SR cells,while overexpressing STIM1 promoted SR by activating SOCE.Mechanistically,STIM1 increased the transcription of SLC7A11 through the SOCE-CaN-NFAT pathway.Subse-quently,up-regulated SLC7A11 increased glutathione synthesis,resulting in ferroptosis insen-sitivity and SR.Furthermore,combining the SOCE inhibitor SKF96365 with sorafenib significantly improved the sensitivity of sR cells to sorafenib both in vitro and in vivo.These findings suggest a potential strategy to overcome acquired resistance to sorafenib in HcC cells. 展开更多
关键词 Ferroptosis Hepatocellular carcinoma SLC7A11 sorafenib resistance STIM1
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Efficacy of radiofrequency ablation combined with sorafenib for treating liver cancer complicated with portal hypertension and prognostic factors
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作者 Li-Min Yang Hong-Juan Wang +4 位作者 Shan-Lin Li Guan-Hua Gan Wen-Wen Deng Yong-Sheng Chang Lian-Feng Zhang 《World Journal of Gastroenterology》 SCIE CAS 2024年第11期1533-1544,共12页
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
关键词 Radiofrequency ablation sorafenib Liver cancer Portal hypertension EFFICACY Prognosis analysis
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Silencing MFN2 Drives WNT/β-catenin Nucleation to Reduce Sorafenib Sensitivity in Hepatocellular Carcinoma Cells
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作者 Chai-ming ZENG Bin SHAO +1 位作者 Yan-ping CHEN Gui-sheng DING 《Current Medical Science》 SCIE CAS 2024年第4期789-798,共10页
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
关键词 mitofusin-2 epithelial-mesenchymal transition sorafenib resistance apoptosis hepatocellular carcinoma
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Cancer-associated fibroblasts derived fibronectin extra domain A promotes sorafenib resistance in hepatocellular carcinoma cells by activating SHMT1
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作者 Yan Dong Yanrong Chen +10 位作者 Yijie Wang Xiang Zhao Ruiyang Zi Jie Hao Qiong Ding Haoran Jiang Xuesong Wang Fanghao Lu Houjie Liang Zhihao Wei Jianjun Li 《Genes & Diseases》 SCIE CSCD 2024年第6期510-524,共15页
Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the... Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the tumor microenvironment.Beyond acting as a physical barrier,it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance.With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation,we discovered that fibronectin extra domain A(FN-EDA)derived from cancer-associated fibroblasts played a critical role in sorafenib resistance.Mechanistically,FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway,thereby countering the oxidative stress induced by sorafenib.Moreover,we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model,which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues,and through the analysis of HCC samples obtained from The Cancer Genome Atlas(TCGA)database.Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients. 展开更多
关键词 Cancer-associated fibroblasts Fibronectin extra domain A Hepatocellular carcinoma Serine hydroxymethyl transferase1 sorafenib resistance
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Tmem39b promotes tumor progression and sorafenib resistance by inhibiting ferroptosis in hepatocellular carcinoma
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作者 MING ZHUANG XUE ZHANG +2 位作者 LU LI LIMING WEN JIAMIN QIN 《Oncology Research》 SCIE 2024年第8期1347-1357,共11页
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
关键词 TMEM39b sorafenib Ferroptosis Hepatocellular carcinoma
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The flavonoids from Pentorum chinense Pursh.mediates ferroptosis to alleviate sorafenib-induced liver injury in BRL-3A cells
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作者 Di Yang Bo-Wen Zhang +6 位作者 Shan Lei Jin-Tao Li Mei-Hao Peng Jia-Qing Liao Xue Tang Qi Zhao Qiu-Xia Lu 《Traditional Medicine Research》 2024年第2期18-26,共9页
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
关键词 sorafenib Pentorum chinense Pursh. ferroptosis oxidative stress NRF2
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Luteolin alleviates sorafenib-induced ferroptosis of BRL-3A cells through modulation of the Nrf2/GPX4 signaling pathway
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作者 Bo-Wen Zhang Di Yang +5 位作者 Jin-Tao Li Mei-Hao Peng Jia-Qing Liao Qi Zhao Yi-Xi Yang Qiu-Xia Lu 《Traditional Medicine Research》 2024年第10期1-9,共9页
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
关键词 LUTEOLIN sorafenib liver injury ferroptosis Nrf2/GPX4
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Sorafenib plus transarterial chemoembolization vs sorafenib alone for patients with advanced hepatocellular carcinoma: A systematic review and meta-analysis
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作者 Hong-Jie Yang Bin Ye +2 位作者 Jia-Xu Liao Lei Lei Kai Chen 《World Journal of Hepatology》 2024年第1期91-102,共12页
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
关键词 Hepatocellular carcinoma sorafenib Transarterial chemoembolization Systematic review META-ANALYSIS
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Charcoal Nanoparticles as a Delivery System for Doxorubicin and Sorafenib in Treatment of Hepatocellular Carcinoma
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作者 Aisha Elgurashi Abdulla Toga Khalid Mohamed Gader +3 位作者 Marvit Osman Widdatallah Omer Abdullah E. Gouda Samah Mamdouh Mohamed A. Shemis 《Advances in Nanoparticles》 CAS 2024年第3期45-60,共16页
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
关键词 Activated Charcoal Nanoparticles (ACNP) Drug Delivery System sorafenib and Doxorubicin Hepatocellular Cancer Stem Cells
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Inhibition of mTOR enhances sorafenib-induced activated HSC ferroptosis
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作者 LI Jia-hao ZHANG Li-jun +3 位作者 PENG Jin-cheng XIE Xian-jiao WANG Guo-kai FANG Ling 《Journal of Hainan Medical University》 CAS 2023年第5期11-19,共9页
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
关键词 sorafenib Liver fibrosis HSC MTOR Ferroptosis
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Physcion increases the sensitivity of hepatocellular carcinoma to sorafenib through miRNA-370/PIM1 axis-regulated glycolysis
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作者 Xiao-Ping Pan Bu-Ren Jiya +1 位作者 Feng Wang Zhu Lan 《World Journal of Gastrointestinal Oncology》 SCIE 2023年第8期1400-1411,共12页
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
关键词 Hepatocellular carcinoma sorafenib resistance PHYSCION GLYCOLYSIS PIM1
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Real-world clinical effectiveness of sorafenib among patients with unresectable hepatocellular carcinoma at two centers in the United States
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作者 Daneng Li Stephen B Gruber +2 位作者 Shrividya Iyer Sanjay Gupta Mohamedtaki Tejani 《World Journal of Gastrointestinal Oncology》 SCIE 2023年第10期1796-1806,共11页
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
关键词 Retrospective observational study sorafenib Hepatocellular carcinoma Clinical effectiveness
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Experimental study on the synergistic inhibition of malignant biological behavior of hepatocellular carcinoma cells by the combination of DMDD and sorafenib
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作者 NONG Ying-dan PHAM THI Thai Hoa +7 位作者 HAN Xiao HE Yong-fei LIANG Tian-yi LU Chun-miao TANG Li-bo YANG Zi-ye HAN Chuang-ye LUO Xiao-ling 《Journal of Hainan Medical University》 CAS 2023年第13期15-22,共8页
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
关键词 Hepatocellular carcinoma DMDD sorafenib INHIBITION Serine synthesis pathway
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LINC00662 affects the sensitivity of hepatocellular carcinoma cells to sorafenib drug by regulating miR-106a-5p/CAV1 axis
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作者 CHEN Bo‑cen LIANG Na +3 位作者 YAN Dong‑jing CHEN Tong XIAO Man CAI Wang‑wei 《Journal of Hainan Medical University》 CAS 2023年第11期8-14,共7页
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
关键词 LINC00662 Liver cancer sorafenib resistance miR-106a-5p CAV1
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Sorafenib通过抑制TGF-β/Smad途径延缓肾纤维化的研究 被引量:8
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作者 贾利宁 马晓桃 +2 位作者 杨阳 付荣国 桂保松 《西安交通大学学报(医学版)》 CAS CSCD 北大核心 2016年第3期378-382,398,共6页
目的探讨sorafenib减轻肾纤维化的作用及机制。方法用低、中、高剂量sorafenib分别给单侧输尿管梗阻(UUO)模型大鼠灌胃或干预经TGF-β1刺激的NRK-52E细胞。HE染色观察各组肾组织纤维化情况,免疫荧光染色检测肾组织及NRK-52E细胞α-SMA、... 目的探讨sorafenib减轻肾纤维化的作用及机制。方法用低、中、高剂量sorafenib分别给单侧输尿管梗阻(UUO)模型大鼠灌胃或干预经TGF-β1刺激的NRK-52E细胞。HE染色观察各组肾组织纤维化情况,免疫荧光染色检测肾组织及NRK-52E细胞α-SMA、E-cadherin的表达情况。用流式细胞术测定各组NRK-52E细胞周期。Western blot检测各组NRK-52E细胞中Smad3和p-Smad3的表达变化。结果 HE染色结果显示,与UUO模型组相比,sorafenib治疗组肾间质纤维化明显减轻,小管萎缩、炎细胞浸润较轻(P<0.05);与对照组比较,sorafenib治疗组E-cadherin在NRK-52E细胞和肾组织中表达均增加,而α-SMA表达均降低(P<0.05);流式细胞术分析发现细胞周期停滞于G0/G1期的细胞数明显增加,而进入G2、S期的细胞数明显减少(P<0.05);与对照组比较,sorafenib干预组p-Smad3蛋白在NRK-52E细胞中表达降低,且与sorafenib剂量呈正相关(P<0.05)。结论 sorafenib具有抗肾脏纤维化作用,主要通过TGF-β/Smad途径发挥作用,可能为治疗肾纤维化提供一种早期干预的新手段。 展开更多
关键词 索拉菲尼(sorafenib) 肾纤维化 间质上皮细胞转分化 TGF-Β SMAD3
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Sorafenib联合化疗治疗进展期肾癌Ⅱ期临床研究 被引量:7
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作者 廉红云 迟志宏 +4 位作者 袁香庆 斯璐 崔传亮 盛锡楠 郭军 《肿瘤学杂志》 CAS 2008年第5期358-361,共4页
[目的]探讨Sorafenib联合吉西他滨、5-Fu治疗晚期肾细胞癌的疗效及安全性。[方法]入组转移性肾细胞癌患者19例,其中既往细胞因子治疗失败者15例。化疗方案采用吉西他滨1g/m2,d1,8,5-Fu400mg/m2静脉推注d1,随后5-Fu2.1g/m246h化疗泵泵入,... [目的]探讨Sorafenib联合吉西他滨、5-Fu治疗晚期肾细胞癌的疗效及安全性。[方法]入组转移性肾细胞癌患者19例,其中既往细胞因子治疗失败者15例。化疗方案采用吉西他滨1g/m2,d1,8,5-Fu400mg/m2静脉推注d1,随后5-Fu2.1g/m246h化疗泵泵入,每4周为1个周期。同时Sorafenib治疗,400mg/次,口服,2次/d,持续使用至疾病进展或出现不可耐受的毒副反应。[结果]19例患者均可评价疗效。客观有效率37%(7/19),临床受益率79%(15/19)。6个月的PFS百分比为37%(7/19),并且该7例患者目前均无疾病进展。常见毒副作用为Ⅲ~Ⅳ度的骨髓抑制、Ⅱ度以上的手足综合征、Ⅱ度以上的胃肠道反应、Ⅱ度以上的皮疹、Ⅰ~Ⅱ度脱发、Ⅰ~Ⅱ度高血压。[结论]研究提示Sorafenib联合吉西他滨,5-Fu治疗晚期肾细胞癌表现出了较好的疗效和一定的安全性。 展开更多
关键词 肾肿瘤 药物疗法 sorafenib
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Sorafenib联合紫杉醇不同给药顺序作用于人肝癌细胞BEL-7402的效应 被引量:1
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作者 李娜 张阳 +1 位作者 吴涛 李曼 《癌症》 SCIE CAS CSCD 北大核心 2009年第8期838-843,共6页
背景与目的:Sorafenib是一种多靶点的抗肿瘤药物,其治疗原发性肝癌的疗效已经初步得到证实。本研究应用Sorafenib与紫杉醇(paclitaxel,TAX)联合,观察两药不同的给药顺序作用于人肝癌细胞BEL-7402的不同效应,初步探讨产生这种差异的机制... 背景与目的:Sorafenib是一种多靶点的抗肿瘤药物,其治疗原发性肝癌的疗效已经初步得到证实。本研究应用Sorafenib与紫杉醇(paclitaxel,TAX)联合,观察两药不同的给药顺序作用于人肝癌细胞BEL-7402的不同效应,初步探讨产生这种差异的机制。方法:采用MTT法检测Sorafenib与紫杉醇单药作用于BEL-7402细胞的IC50。流式细胞术检测Sorafenib与紫杉醇不同给药顺序作用后,BEL-7402细胞周期和凋亡率的变化。Western blot检测不同给药顺序作用后的BEL-7402细胞Bcl-2的表达情况。结果:Sorafenib和紫杉醇单药作用于BEL-7402细胞48h的IC50分别为(2.43±0.32)μg/mL、(1.89±0.72)μg/mL。分析Sorafenib、紫杉醇单药,先用紫杉醇再加入Sorafenib,先用Sorafenib再加入紫杉醇及紫杉醇与Sorafenib同时作用后BEL-7402细胞周期及凋亡率的变化,结果显示:①Sorafenib主要将细胞阻滞在S期,而紫杉醇主要将细胞阻滞在G2-M期。②先用紫杉醇再给予Sorafenib组细胞S期及G2-M期均有延长,且较其他组获得较高的凋亡率(36.43±2.29)%(P<0.01)。Western blot显示先用紫杉醇再给予Sorafenib组BEL-7402细胞的Bcl-2表达的水平最低。结论:Sorafenib联合紫杉醇不同给药顺序作用于BEL-7402细胞,先应用紫杉醇诱导再序贯给予Sorafenib时细胞凋亡率更高;产生这种不同效应的可能机制为两种药物作用于不同的细胞周期,以及不同给药方法后的Bcl-2的表达水平不同。 展开更多
关键词 肝肿瘤/药理学 sorafenib(索拉非尼) 紫杉醇 用药顺序 BCL-2
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Sorafenib对肝癌肝移植术后肿瘤转移复发大鼠的治疗作用 被引量:2
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作者 邹伟伟 杨振林 程凯 《中国现代普通外科进展》 CAS 2011年第2期85-89,共5页
目的:探讨Sorafenib对肝癌肝移植术后肿瘤转移复发大鼠的治疗作用。方法:Walker-256癌细胞于Wistar大鼠门静脉注射,模拟大鼠肝癌肝移植术后肿瘤转移复发模型,术后随机分为4组(n=16):对照组、Sorafenib低剂量组、Sorafenib中剂量组、Sora... 目的:探讨Sorafenib对肝癌肝移植术后肿瘤转移复发大鼠的治疗作用。方法:Walker-256癌细胞于Wistar大鼠门静脉注射,模拟大鼠肝癌肝移植术后肿瘤转移复发模型,术后随机分为4组(n=16):对照组、Sorafenib低剂量组、Sorafenib中剂量组、Sorafenib高剂量组,另选取5只正常Wistar大鼠作为正常组。Sorafenib各剂量组和对照组分别于术后20 d各随机选取8只,抽取静脉血,采用酶联免疫吸附方法(ELISA)检测大鼠血清中血管内皮生长因子(VEGF)含量,检测大鼠血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)、胆红素(TB)含量;取大鼠肝脏,常规甲醛固定、制作石蜡切片,HE染色,常规镜下观察;采用免疫组织化学方法计数肝脏微血管密度(MVD);观察Sorafenib各剂量组及对照组剩余8只大鼠生存时间。结果:Sorafenib各剂量组及对照组大鼠肝脏均出现了肿瘤转移复发,但Sorafenib各剂量组大鼠肝脏癌灶坏死程度较对照组明显,癌灶周边肝脏细胞受累坏死程度较对照组轻;Sorafenib各剂量组大鼠血清VEGF、ALT、AST、TB浓度均低于对照组(P<0.05);Sorafenib各剂量组大鼠肝脏MVD计数低于对照组(P<0.05);Sorafenib中、高剂量组大鼠存活率高于对照组(P<0.05)。结论:Sorafenib可以抑制肝癌肝移植术后肿瘤转移复发大鼠癌灶微血管生成,同时减轻癌灶对正常肝细胞的损害作用,延长肝癌肝移植术后肿瘤转移复发大鼠的生存时间,对肝癌肝移植术后肿瘤转移复发大鼠起到一定的治疗作用。 展开更多
关键词 大鼠 Wistar 肝肿瘤 肝移植 sorafenib
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Sorafenib对前列腺癌DU145细胞的抑制作用的研究
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作者 高锐 毛厚平 +3 位作者 周辉良 吕夷松 江涛 许宁 《现代泌尿生殖肿瘤杂志》 2010年第6期347-349,共3页
目的观察索拉非尼(Sorafenib)对雄激素非依赖性前列腺癌DU145细胞的抑制作用。方法用不同浓度Sorafenib处理前列腺癌DU145细胞24、48和72h后,MTT法检测Sor-afenib对DU145细胞的抑制作用,流式细胞仪检测细胞凋亡变化,Western blot检测不... 目的观察索拉非尼(Sorafenib)对雄激素非依赖性前列腺癌DU145细胞的抑制作用。方法用不同浓度Sorafenib处理前列腺癌DU145细胞24、48和72h后,MTT法检测Sor-afenib对DU145细胞的抑制作用,流式细胞仪检测细胞凋亡变化,Western blot检测不同浓度Sor-afenib处理72h后DU145细胞内ERK和Bcl-2的表达。结果 Sorafenib能显著抑制DU145细胞的体外生长,呈时间与剂量依赖性。DU145细胞凋亡率随着Sorafenib剂量的增加而增大,具有良好的量效关系(P<0.01);Sorafenib处理DU145细胞72h后,ERK和Bcl-2蛋白的表达明显下调(P<0.01)。结论 Sorafenib抑制DU145细胞增殖、诱导细胞凋亡,可显著抑制雄激素非依赖性前列腺癌细胞的体外生长。 展开更多
关键词 sorafenib 前列腺肿瘤
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浅谈新型靶向药物Sorafenib对肿瘤治疗的研究
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作者 陆群英 许雪 +4 位作者 吴原 刘明章 钟华杰 戴利成 宋颖劼 《海峡药学》 2015年第2期189-191,共3页
新型靶向药物Sorafenib是一种多靶点的生物制药,被临床前研究和临床实验证实具有广泛的抗肿瘤作用。本文从探讨了其作用机理,并总结了其在肾细胞癌,肝癌,非小细胞肺癌等癌症中的临床治疗及实验数据,认为其具有潜在的广谱抗肿瘤作用,为... 新型靶向药物Sorafenib是一种多靶点的生物制药,被临床前研究和临床实验证实具有广泛的抗肿瘤作用。本文从探讨了其作用机理,并总结了其在肾细胞癌,肝癌,非小细胞肺癌等癌症中的临床治疗及实验数据,认为其具有潜在的广谱抗肿瘤作用,为肿瘤的生物靶向治疗翻开了新的篇章。 展开更多
关键词 sorafenib 靶向药物 肿瘤治疗
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