【《索拉非尼的研究进展文献综述》2500字】

索拉非尼的研究进展文献综述1.1索拉非尼的简介及抗肝癌机制索拉非尼（Sorafenib,SF）是一种口服多激酶抑制剂（MKI），在改善患者总生存期率(OS)和无进展生存期（PFS）显示一个满意的效果ADDINEN.CITEADDINEN.CITE.DATA[20]。根据SHARP试验，SF与安慰剂组相比，患者的生存期延长了2.8个月，中位总生存期为10.7个月，而安慰剂组仅为7.9个月。同时一些临床前和临床研究报告了SF对其他几种肿瘤也可有效地抑制肿瘤生长，如乳腺癌、恶性黑色素瘤、甲状腺肿瘤、前列腺癌ADDINEN.CITEADDINEN.CITE.DATA[21-25]。体外研究结果表明，SF可抑制多种细胞内激酶（RAF、野生型和突变型BRAF）和细胞表面激酶（KIT、FLT3、RET、VEGFR1-3和PDGFRb）来抑制肿瘤细胞增殖，促进细胞凋亡以及预防血管生成（图1-3）。另外，一些研究表明SF尼还可通过活化的c-Kit可以调节RAF/MEK/ERK级联和磷酸肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路的转录，从而有助于SF的抗癌活性。但是PI3k/AKT途径的活化同时也激活了MAPK级联反应的逃逸途径，从而导致SF耐药。不可否认的是，肿瘤细胞对SF的耐药性已成为发挥其抗HCC有效性的主要障碍。图1-3索拉非尼通过靶向肿瘤细胞增殖，凋亡和血管生成的作用机制ADDINEN.CITEADDINEN.CITE.DATA[26]。1.2铁死亡在索拉非尼抗HCC中的作用SF除了上述提到的作为多激酶抑制剂之外，最新研究表明SF还可作为铁死亡（Ferroptosis）诱导剂。长期以来，凋亡被认为是程序性细胞死亡的唯一途径。然而，由于癌细胞对诱导凋亡的药物具有获得性或内在抗药性，导致肿瘤中凋亡诱导的有效性受到限制ADDINEN.CITE<EndNote><Cite><Author>Su</Author><Year>2016</Year><RecNum>58</RecNum><DisplayText><styleface="superscript">[27]</style></DisplayText><record><rec-number>58</rec-number><foreign-keys><keyapp="EN"db-id="ptwsza2roz99vkexa0qpdzd9r5xfzs5rzsd0"timestamp="1618845326">58</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Su,Z.</author><author>Yang,Z.</author><author>Xie,L.</author><author>DeWitt,J.P.</author><author>Chen,Y.</author></authors></contributors><auth-address>DepartmentofBiochemistryandMolecularBiology,MedicalSchool,SoutheastUniversity,Nanjing,Jiangsu210009,China. DepartmentofCellBiology,HarvardMedicalSchool,Boston,MA02115,USA. BoneandSoftTissueTumorsResearchCenterofYunnanProvince,DepartmentofOrthopaedics,TheThirdAffiliatedHospitalofKunmingMedicalUniversity(TumorHospitalofYunnanProvince),Kunming,Yunnan650118,China. KeyLaboratoryofAnimalModelsandHumanDiseaseMechanisms,KunmingInstituteofZoology,ChineseAcademyofSciences,Kunming,Yunnan650223,China.</auth-address><titles><title>Cancertherapyinthenecroptosisera</title><secondary-title>CellDeathDiffer</secondary-title></titles><periodical><full-title>CellDeathDiffer</full-title></periodical><pages>748-56</pages><volume>23</volume><number>5</number><edition>2016/02/27</edition><keywords><keyword>AntineoplasticAgents/*pharmacology</keyword><keyword>Apoptosis/*drugeffects</keyword><keyword>Humans</keyword><keyword>Necrosis</keyword><keyword>Neoplasms/*drugtherapy/*pathology</keyword></keywords><dates><year>2016</year><pub-dates><date>May</date></pub-dates></dates><isbn>1476-5403(Electronic) 1350-9047(Linking)</isbn><accession-num>26915291</accession-num><urls><related-urls><url>/pubmed/26915291</url></related-urls></urls><custom2>PMC4832112</custom2><electronic-resource-num>10.1038/cdd.2016.8</electronic-resource-num></record></Cite></EndNote>[27]。近年来，研究表明铁死亡参与了许多疾病的发生和发展，已成为相关疾病的治疗和预后改善的研究重点和热点，由于其。在癌症治疗中，铁死亡已被证明可有效杀死癌细胞，特别是对于那些表达突变的小GTP酶的癌症。铁死亡又被定义为铁催化形式的调节性坏死，其通过多不饱和脂肪酸（PUFAs）的过度过氧化而发生。铁死亡的产生原因是细胞膜上的多不饱和脂肪酸（PL-PUFA-OH）可被脂氧合酶和ROS氧化形成有毒的脂质过氧化物（PL-PUFA-OOH）ADDINEN.CITE<EndNote><Cite><Author>Cheng</Author><Year>2007</Year><RecNum>59</RecNum><DisplayText><styleface="superscript">[28]</style></DisplayText><record><rec-number>59</rec-number><foreign-keys><keyapp="EN"db-id="ptwsza2roz99vkexa0qpdzd9r5xfzs5rzsd0"timestamp="1618849493">59</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Cheng,Z.</author><author>Li,Y.</author></authors></contributors><auth-address>TheKeyLaboratoryofBioorganic&MolecularEngineering,CollegeofChemistry&MolecularEngineering,PekingUniversity,Beijing,China100871.</auth-address><titles><title>Whatisresponsiblefortheinitiatingchemistryofiron-mediatedlipidperoxidation:anupdate</title><secondary-title>ChemRev</secondary-title></titles><periodical><full-title>ChemRev</full-title></periodical><pages>748-66</pages><volume>107</volume><number>3</number><edition>2007/03/01</edition><keywords><keyword>Animals</keyword><keyword>Catalysis</keyword><keyword>Humans</keyword><keyword>Iron/*chemistry/*metabolism</keyword><keyword>*LipidPeroxidation</keyword><keyword>LipidPeroxides/*chemistry/metabolism</keyword><keyword>MolecularStructure</keyword><keyword>ReactiveOxygenSpecies/metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0009-2665(Print) 0009-2665(Linking)</isbn><accession-num>17326688</accession-num><urls><related-urls><url>/pubmed/17326688</url></related-urls></urls><electronic-resource-num>10.1021/cr040077w</electronic-resource-num></record></Cite></EndNote>[28]，导致细胞膜脂质中多不饱和脂肪酸的分解ADDINEN.CITE<EndNote><Cite><Author>Cheng</Author><Year>2007</Year><RecNum>59</RecNum><DisplayText><styleface="superscript">[28]</style></DisplayText><record><rec-number>59</rec-number><foreign-keys><keyapp="EN"db-id="ptwsza2roz99vkexa0qpdzd9r5xfzs5rzsd0"timestamp="1618849493">59</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Cheng,Z.</author><author>Li,Y.</author></authors></contributors><auth-address>TheKeyLaboratoryofBioorganic&MolecularEngineering,CollegeofChemistry&MolecularEngineering,PekingUniversity,Beijing,China100871.</auth-address><titles><title>Whatisresponsiblefortheinitiatingchemistryofiron-mediatedlipidperoxidation:anupdate</title><secondary-title>ChemRev</secondary-title></titles><periodical><full-title>ChemRev</full-title></periodical><pages>748-66</pages><volume>107</volume><number>3</number><edition>2007/03/01</edition><keywords><keyword>Animals</keyword><keyword>Catalysis</keyword><keyword>Humans</keyword><keyword>Iron/*chemistry/*metabolism</keyword><keyword>*LipidPeroxidation</keyword><keyword>LipidPeroxides/*chemistry/metabolism</keyword><keyword>MolecularStructure</keyword><keyword>ReactiveOxygenSpecies/metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0009-2665(Print) 0009-2665(Linking)</isbn><accession-num>17326688</accession-num><urls><related-urls><url>/pubmed/17326688</url></related-urls></urls><electronic-resource-num>10.1021/cr040077w</electronic-resource-num></record></Cite></EndNote>[28]，最终细胞会由于细胞膜破裂而死亡。最重要的是，铁死亡的发生与铁离子存在密不可分ADDINEN.CITEADDINEN.CITE.DATA[29]。此外，近年来的临床和基础研究均表明，铁死亡在肝癌的发生扮演着重要角色ADDINEN.CITEADDINEN.CITE.DATA[30,31]。许多学者认为，铁死亡是诊断，预防和治疗HCC的潜在靶标，从而为SF在肿瘤中的最佳使用开辟了新途径ADDINEN.CITEADDINEN.CITE.DATA[32]。SF可通过两种主要途径影响铁死亡(图1-4)ADDINEN.CITEADDINEN.CITE.DATA[33]。SF抑制胱氨酸（Cys）/谷氨酸（Glu）反向交换系统（Systemxc-，包含两个膜转运：SLG3A2和SLG7A11），导致内质网应激，减少细胞内谷胱甘肽（GSH）和ROS的积累。由于GSH依赖性脂质修复酶谷胱甘肽过氧化物酶4（GPX-4）可以将有毒的PL-PUFA-OOH转化为无毒的PL-PUFA-OHADDINEN.CITEADDINEN.CITE.DATA[29]。因此，GPX-4可以减少脂质自由基的积累，并防止铁死亡的发生和发展。作为唯一可以将脂质过氧化物转化为多不饱和脂肪酸的谷胱甘肽过氧化物酶，其激活高度依赖于细胞内GSH。然而，GSH在细胞中的合成需要半systemxc-，把细胞内的谷氨酸盐转运至细胞外，而将细胞外的Cys运输进入细胞内ADDINEN.CITEADDINEN.CITE.DATA[30]。因此根据上述机制，可知排出细胞内GSH，抑制systemxc-，抑制GPX-4的活性，并增加细胞内的铁含量措施都可以增强细胞中的脂氧合酶和ROSADDINEN.CITEADDINEN.CITE.DATA[28,29]。然而，研究表明，SF会激活p62-Keap1-NRF2通路，使得NRF2增多，这又会导致GSH的增多，这一过程会衰减铁死亡的发生。因此，SF可与抑制NRF2通路的药物联合进行相关癌症的治疗，这一问题尚需进一步研究。图1-4索拉非尼治疗影响铁死亡的主要机制ADDINEN.CITEADDINEN.CITE.DATA[33]。1.3关于索拉非尼联合治疗的策略除上述所提到肿瘤细胞细胞对SF具有耐药性严重影响其治疗效果外，研究表明只有30％的HCC患者受益于索拉非尼，其中一些人还具有严重的不良副作用ADDINEN.CITEADDINEN.CITE.DATA[34]。因此，迫切需要通过新的治疗方案或策略来改善索拉非尼的治疗效果并使其副作用最小化。众所周知，PI3K/AKT信号传导与MAPK/ERK信号传导通路发生串扰，即PI3K/AKT通路的潜在补偿性激活可能有助于索拉非尼对HCC的耐药性ADDINEN.CITEADDINEN.CITE.DATA[35,36]。例如，长春西汀与索拉非尼的联用能够有效抑制了长春西汀激活的HCC细胞的保护性自噬，抑制了肿瘤细胞的增殖和发展。同时，该药物组合可通过PI3K/蛋白激酶B/GSK-3β逆转索拉非尼的耐药性信号轴，显著增强诱导肝癌细胞凋亡ADDINEN.CITEADDINEN.CITE.DATA[34,37]。此外，许多研究学者通过联合DantroleneADDINEN.CITE<EndNote><Cite><Author>Zakaria</Author><Year>2021</Year><RecNum>108</RecNum><DisplayText><styleface="superscript">[38]</style></DisplayText><record><rec-number>108</rec-number><foreign-keys><keyapp="EN"db-id="ptwsza2roz99vkexa0qpdzd9r5xfzs5rzsd0"timestamp="1620355944">108</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zakaria,S.</author><author>Ansary,A.</author><author>Abdel-Hamid,N.M.</author><author>ElShishtawy,M.M.</author></authors></contributors><auth-address>DepartmentofPharmacologyandToxicologyFacultyofPharmacy,KafrelsheikhUniversity,Kafrelsheikh,33516.Egypt. DepartmentofBiochemistry,FacultyofPharmacy,KafrelsheikhUniversity,Kafrelsheikh,33516.Egypt. DepartmentofBiochemistry,FacultyofPharmacy,MansouraUniversity,Mansoura,35516.Egypt.</auth-address><titles><title>DantrolenePotentiatestheAntineoplasticEffectofSorafenibinHepatocellularCarcinomaviaTargetingCa+2/PI3KSignalingPathway</title><secondary-title>CurrMolPharmacol</secondary-title></titles><periodical><full-title>CurrMolPharmacol</full-title></periodical><edition>2021/02/13</edition><keywords><keyword>ca+2</keyword><keyword>dantrolenesodium</keyword><keyword>dena</keyword><keyword>hcc</keyword><keyword>pi3k</keyword><keyword>sorafenib</keyword></keywords><dates><year>2021</year><pub-dates><date>Jan25</date></pub-dates></dates><isbn>1874-4702(Electronic) 1874-4672(Linking)</isbn><accession-num>33573585</accession-num><urls><related-urls><url>/pubmed/33573585</url></related-urls></urls><electronic-resource-num>10.2174/1874467214666210126110627</electronic-resource-num></record></Cite></EndNote>[38]，3-hydroxyanthranilicacidADDINEN.CITEADDINEN.CITE.DATA[39]，丙戊酸ADDINEN.CITE<EndNote><Cite><Author>Yang</Author><Year>2020</Year><RecNum>112</RecNum><DisplayText><styleface="superscript">[40]</style></DisplayText><record><rec-number>112</rec-number><foreign-keys><keyapp="EN"db-id="ptwsza2roz99vkexa0qpdzd9r5xfzs5rzsd0"timestamp="1620356380">112</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yang,X.</author><author>Liu,J.</author><author>Liang,Q.</author><author>Sun,G.</author></authors></contributors><auth-address>DepartmentofPharmacy,TheFifthPeople'sHospitalofShanghai,FudanUniversity,Shanghai,200240,China.</auth-address><titles><title>ValproicacidreversessorafenibresistancethroughinhibitingactivatedNotch/Aktsignalingpathwayinhepatocellularcarcinoma</title><secondary-title>FundamClinPharmacol</secondary-title></titles><periodical><full-title>FundamClinPharmacol</full-title></periodical><edition>2020/10/06</edition><keywords><keyword>Akt</keyword><keyword>Notch1</keyword><keyword>resistance</keyword><keyword>reverse</keyword><keyword>sorafenib</keyword><keyword>valproicacid</keyword></keywords><dates><year>2020</year><pub-dates><date>Oct4</date></pub-dates></dates><isbn>1472-8206(Electronic) 0767-3981(Linking)</isbn><accession-num>33015852</accession-num><urls><related-urls><url>/pubmed/33015852</url></related-urls></urls><electronic-resource-num>10.1111/fcp.12608</electronic-resource-num></record></Cite></EndNote>[40]这些能够靶向PI3K/AKT通路的药物来增强索拉非尼在肝细胞癌中的抗肿瘤作用，并取得了优异的实验结果。另外研究中，当SF与Pristimerin联用时发现Pristimerin可通过增加肿瘤细胞内ROS产生来增强索拉非尼介导的细胞凋亡，同时实验也表明该组合药物对原发性肝癌细胞生长的抑制作用比单一药物都要强ADDINEN.CITEADDINEN.CITE.DATA[41]。近年来，越来越多研究学者发现SF与天然药物组合也可产生协同作用，从而可以提高抗肿瘤功效，减少副作用并延缓耐药性ADDINEN.CITE<EndNote><Cite><Author>Shrestha</Author><Year>2021</Year><RecNum>106</RecNum><DisplayText><styleface="superscript">[42]</style></DisplayText><record><rec-number>106</rec-number><foreign-keys><keyapp="EN"db-id="ptwsza2roz99vkexa0qpdzd9r5xfzs5rzsd0"timestamp="1620355309">106</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Shrestha,R.</author><author>Prithviraj,P.</author><author>Bridle,K.R.</author><author>Crawford,D.H.G.</author><author>Jayachandran,A.</author></authors></contributors><auth-address>FacultyofMedicine,TheUniversityofQueensland,Brisbane,QLD4120,Australia. GallipoliMedicalResearchInstitute,GreenslopesPrivateHospital,Brisbane,QLD4120,Australia. FionaElseyCancerResearchInstitute,Ballarat,VIC3350,Australia. SchoolofScience,PsychologyandSports,FederationUniversityAustralia,Ballarat,VIC3350,Australia.</auth-address><titles><title>CombinedInhibitionofTGF-beta1-InducedEMTandPD-L1SilencingRe-SensitizesHepatocellularCarcinomatoSorafenibTreatment</title><secondary-title>JClinMed</secondary-title></titles><periodical><full-title>JClinMed</full-title></periodical><volume>10</volume><number>9</number><edition>2021/05/01</edition><keywords><keyword>Emt</keyword><keyword>Pd-l1</keyword><keyword>hepatocellularcarcinoma</keyword><keyword>immunecheckpoint</keyword><keyword>sorafenib</keyword></keywords><dates><year>2021</year><pub-dates><date>Apr27</date></pub-dates></dates><isbn>2077-0383(Print) 2077-0383(Linking)</isbn><accession-num>33925488</accession-num><urls><related-urls><url>/pubmed/33925488</url></related-urls></urls><electronic-resource-num>10.3390/jcm10091889</electronic-resource-num></record></Cite></EndNote>[42]。例如，将SF与一种天然药物提取物辣椒素（8-甲基N-香草基-6壬烯酰胺）联合治疗可有效抑制HCC细胞的生长，侵袭和转移，并以协同方式诱导自噬。该药物组合协同抗肿瘤作用机制与抑制EGFR和PI3K/Akt/mTOR信号通路相关，即通过增加caspase-3、Bax和PARP-1活性，减少Bcl-2表达来诱导细胞凋亡，同时上调beclin-1和LC3A/BII水平，促进P62降解来诱导细胞自噬。Lu等人ADDINEN.CITEADDINEN.CITE.DATA[43]发现20（S）-人参皂苷Rg3可通过显着抑制HCC细胞的生长而增强了SF的细胞毒性作用。由于SF诱导了肝癌细胞中Akt的活化降低其抑制肿瘤效果，然而当SF与20（S）-人参皂苷Rg3联合使用时，磷酸化Akt和磷酸化PDK1的表达显着降低。值得令人关注的是，研究发现通过五环三萜类齐墩果酸（OA）联合治疗以持续的方式触发细胞损伤并抑制长期克隆形成的存活，有效地改善了SF的治疗效果ADDINEN.CITEADDINEN.CITE.DATA[44]。此外，研究表明SF/OA协同治疗可促进活性氧（ROS）水平的显着提高并且共同触发线粒体介导的凋亡细胞死亡ADDINEN.CITEADDINEN.CITE.DATA[44,45]。最重要的是，细胞内ROS的积累可诱导细胞死亡。因此，OA代表了一种通过氧化应激增加HCC细胞对SF敏感性的新颖方法。三萜类化合物是一组广泛而重要的化合物，该类化合物具有相似的药理特性，即也表明了三萜类化合物与SF联合治疗有望增强其抗肿瘤效果，减少其不良副作用。参考文献[1] SUNGH,FERLAYJ,SIEGELRL,etal.Globalcancerstatistics2020:GLOBOCANestimatesofincidenceandmortalityworldwidefor36cancersin185countries[J].CACancerJClin,2021.[2] SUND,CAOM,LIH,etal.CancerburdenandtrendsinChina:AreviewandcomparisonwithJapanandSouthKorea[J].ChinJCancerRes,2020,32(2):129-39.[3] DINGH,HUH,TIANF,etal.AdualimmunesignatureofCD8+TcellsandMMP9improvesthesurvivalofpatientswithhepatocellularcarcinoma[J].BiosciRep,2021,41(3).[4] LIUPH,HSUCY,HSIACY,etal.Prognosisofhepatocellularcarcinoma:Assessm