AbMole小讲堂丨Vorinostat（SAHA,MK0683）：组蛋白去乙酰化酶（HDAC）抑制剂在表观遗传学、肿瘤和神经生物学中的应用

AbMole小讲堂丨Vorinostat（SAHA,MK0683）：组蛋白去乙酰化酶（HDAC）抑制剂在表观遗传学、肿瘤和神经生物学中的应用Vorinostat(SAHA,MK0683，AbMole，M1780)是一种广谱的泛组蛋白去乙酰化酶抑制剂（HDACi）。其化学结构属于丁二酰亚胺羟肟酸类化合物，能够通过直接与HDACs结合并抑制其活性，增加乙酰化组蛋白的积累，从而调节细胞中的基因表达，并影响多个信号通路。此外，Vorinostat（MK0683）还具有细胞周期阻滞、凋亡、抑制血管生成等生物活性。研究表明，Vorinostat还可双向调控应激反应基因的表达（如sod-3、hsp-16.2、skn-1等），Vorinostat在低浓度时上调上述基因的表达，而在高浓度（10μM）时则呈现抑制或中性效应，显示出剂量依赖性的表观遗传调控特性ADDINEN.CITEADDINEN.CITE.DATA[1]。Vorinostat还可通过降低Akt信号通路的表达水平，诱导细胞周期阻滞和程序性死亡ADDINEN.CITEADDINEN.CITE.DATA[2]。此外，Vorinostat还可下调多种表观遗传调控酶（如EZH2、SUV39H1/2、DOT1L等）的表达，说明其对表观遗传调控网络具有广泛的影响ADDINEN.CITEADDINEN.CITE.DATA[3]。在科研应用中，Vorinostat(SAHA)展现出多方面的潜力。首先Vorinostat可抑制多种肿瘤细胞的增殖，例如结肠癌细胞（HCT116、HT29）ADDINEN.CITEADDINEN.CITE.DATA[4]、胰腺癌细胞（AsPC-1）ADDINEN.CITE<EndNote><Cite><Author>Sanaei</Author><Year>2021</Year><RecNum>1304</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>1304</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1762151706">1304</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sanaei,M.</author><author>Kavoosi,F.</author></authors></contributors><auth-address>ResearchCenterforNon-CommunicableDiseases,JahromUniversityofMedicalSciences,Jahrom,I.R.Iran.</auth-address><titles><title>EffectofvorinostatonINK4familyandHDACs1,2,and3inpancreaticcancerandhepatocellularcarcinoma</title><secondary-title>ResPharmSci</secondary-title><alt-title>Researchinpharmaceuticalsciences</alt-title></titles><periodical><full-title>ResPharmSci</full-title><abbr-1>Researchinpharmaceuticalsciences</abbr-1></periodical><alt-periodical><full-title>ResPharmSci</full-title><abbr-1>Researchinpharmaceuticalsciences</abbr-1></alt-periodical><pages>260-268</pages><volume>16</volume><number>3</number><edition>2021/07/06</edition><keywords><keyword>Cyclin-dependentkinaseinhibitors</keyword><keyword>Neoplasms</keyword><keyword>Vorinostat.</keyword></keywords><dates><year>2021</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1735-5362(Print) 1735-5362</isbn><accession-num>34221059</accession-num><urls></urls><custom2>PMC8216159</custom2><electronic-resource-num>10.4103/1735-5362.314824</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[5]、肝癌细胞（LCL-PI11）ADDINEN.CITE<EndNote><Cite><Author>Sanaei</Author><Year>2021</Year><RecNum>1304</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>1304</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1762151706">1304</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sanaei,M.</author><author>Kavoosi,F.</author></authors></contributors><auth-address>ResearchCenterforNon-CommunicableDiseases,JahromUniversityofMedicalSciences,Jahrom,I.R.Iran.</auth-address><titles><title>EffectofvorinostatonINK4familyandHDACs1,2,and3inpancreaticcancerandhepatocellularcarcinoma</title><secondary-title>ResPharmSci</secondary-title><alt-title>Researchinpharmaceuticalsciences</alt-title></titles><periodical><full-title>ResPharmSci</full-title><abbr-1>Researchinpharmaceuticalsciences</abbr-1></periodical><alt-periodical><full-title>ResPharmSci</full-title><abbr-1>Researchinpharmaceuticalsciences</abbr-1></alt-periodical><pages>260-268</pages><volume>16</volume><number>3</number><edition>2021/07/06</edition><keywords><keyword>Cyclin-dependentkinaseinhibitors</keyword><keyword>Neoplasms</keyword><keyword>Vorinostat.</keyword></keywords><dates><year>2021</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1735-5362(Print) 1735-5362</isbn><accession-num>34221059</accession-num><urls></urls><custom2>PMC8216159</custom2><electronic-resource-num>10.4103/1735-5362.314824</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[5]、头颈部鳞癌（HNSCC）等ADDINEN.CITEADDINEN.CITE.DATA[6]。Vorinostat还可用于抑制寄生虫，其机制同样涉及原虫细胞中HDAC的抑制ADDINEN.CITEADDINEN.CITE.DATA[7]。值得注意的是，组织转谷氨酰胺酶（TG2）的活性状态会影响细胞对Vorinostat的敏感性。研究发现TG2活性的抑制可增强Vorinostat的抗增殖效应，而TG2过表达则导致细胞耐受性的获得，提示TG2是Vorinostat耐受机制中的关键靶点ADDINEN.CITEADDINEN.CITE.DATA[8]。在神经保护领域，Vorinostat可逆转β淀粉样蛋白（AmyloidβProtein）诱导的神经损伤，该生物学活性涉及对AKT-MDM2-p53通路的调控ADDINEN.CITE<EndNote><Cite><Author>Meng</Author><Year>2019</Year><RecNum>1308</RecNum><DisplayText><styleface="superscript">[9]</style></DisplayText><record><rec-number>1308</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1762152304">1308</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Meng,J.</author><author>Li,Y.</author><author>Zhang,M.</author><author>Li,W.</author><author>Zhou,L.</author><author>Wang,Q.</author><author>Lin,L.</author><author>Jiang,L.</author><author>Zhu,W.</author></authors></contributors><auth-address>DepartmentofGeneralMedicine,SecondAffiliatedHospitalofHarbinMedicalUniversity,Harbin,China. DepartmentofPharmacy,FourthAffiliatedHospitalofHarbinMedicalUniversity,Harbin,China. DepartmentofPharmacy,SecondAffiliatedHospitalofHarbinMedicalUniversity,Harbin,China.</auth-address><titles><title>Acombinationofcurcumin,vorinostatandsilibininreversesAβ-inducednervecelltoxicityviaactivationofAKT-MDM2-p53pathway</title><secondary-title>PeerJ</secondary-title><alt-title>PeerJ</alt-title></titles><periodical><full-title>PeerJ</full-title><abbr-1>PeerJ</abbr-1></periodical><alt-periodical><full-title>PeerJ</full-title><abbr-1>PeerJ</abbr-1></alt-periodical><pages>e6716</pages><volume>7</volume><edition>2019/05/16</edition><keywords><keyword>Alzheimer’sdisease</keyword><keyword>Amyloidbeta</keyword><keyword>Curcumin</keyword><keyword>Silibinin</keyword><keyword>Vorinostat</keyword></keywords><dates><year>2019</year></dates><isbn>2167-8359(Print) 2167-8359</isbn><accession-num>31086728</accession-num><urls></urls><custom2>PMC6487801</custom2><electronic-resource-num>10.7717/peerj.6716</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[9]。Transcriptionalactivityofhistonedeacetylase(HDAC)inhibitorsADDINEN.CITE<EndNote><Cite><Author>Parveen</Author><Year>2023</Year><RecNum>1216</RecNum><DisplayText><styleface="superscript">[10]</style></DisplayText><record><rec-number>1216</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760679395">1216</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Parveen,R.</author><author>Harihar,D.</author><author>Chatterji,B.P.</author></authors></contributors><auth-address>FacultyofMedicineandHealthSciences,TampereUniversity,Tampere,Finland. SchoolofEngineeringSciencesinChemistry,BiotechnologyandHealth,KTHRoyalInstituteofTechnology,Stockholm,Sweden. FacultyofScience,AssamDownTownUniversity,Guwahati,India.</auth-address><titles><title>Recenthistonedeacetylaseinhibitorsincancertherapy</title><secondary-title>Cancer</secondary-title><alt-title>Cancer</alt-title></titles><periodical><full-title>Cancer</full-title><abbr-1>Cancer</abbr-1></periodical><alt-periodical><full-title>Cancer</full-title><abbr-1>Cancer</abbr-1></alt-periodical><pages>3372-3380</pages><volume>129</volume><number>21</number><edition>2023/08/10</edition><keywords><keyword>HDACinhibitors</keyword><keyword>HDACidrugs</keyword><keyword>Ptcl</keyword><keyword>cancer</keyword><keyword>combinationaltherapy</keyword><keyword>patents</keyword></keywords><dates><year>2023</year><pub-dates><date>Nov1</date></pub-dates></dates><isbn>0008-543x</isbn><accession-num>37560925</accession-num><urls></urls><electronic-resource-num>10.1002/cncr.34974</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[10].范例详解BMCCancer.2016Nov7;16(1):857.科研人员在该文章中探究了Vorinostat对小细胞肺癌（SCLC）的抑制作用及联合抑制方案的开发。研究通过体外（H209、H146细胞系）和体内（H209异种移植裸鼠）实验，证实Vorinostat（HDAC抑制剂）与顺铂（Cisplatin）联合或与Etoposide(VP-16-213)联合使用时，能比单一处理组更显著地抑制肿瘤细胞的活力、并诱导凋亡（激活caspase-3、促进PARP裂解），以及诱导肿瘤细胞周期的S期阻滞，同时提高组蛋白H3和α-微管蛋白的乙酰化水平并持续抑制胸苷酸合成酶（TS）表达。本文的核心研究对象Vorinostat(SAHA,MK0683，AbMole，M1780)由AbMole提供。CellcycleprogressionanalysisofvorinostatincombinationwithcisplatininSCLCcellsADDINEN.CITEADDINEN.CITE.DATA[11].参考文献及鸣谢ADDINEN.REFLIST[1]S.Huang,H.Shi,Z.Shi,etal.,Vorinostat,apotentialhormetin,extendslifespanandenhancesstressresistanceviatheSKN-1pathwayinCaenorhabditiselegans,Biogerontology26(3)(2025)97.[2]S.Takeuchi,T.Hase,S.Shimizu,etal.,PhaseIstudyofvorinostatwithgefitinibinBIMdeletionpolymorphism/epidermalgrowthfactorreceptormutationdouble-positivelungcancer,Cancerscience111(2)(2020)561-570.[3]V.Maksimova,J.Makus,V.Popova,etal.,HistoneMethyltransferasesasaNewTargetforEpigeneticActionofVorinostat,Biochemistry.Biokhimiia88(7)(2023)968-978.[4]M.Yousefian,M.Hashemi,V.Eskandarpour,etal.,Newindolin-2-ones,possessingsunitinibscaffoldasHDACinhibitorsandanti-canceragentswithpotentialVEGFRinhibitionactivity;design,synthesisandbiologicalevaluation,Bioorganicchemistry156(2025)108231.[5]M.Sanaei,F.Kavoosi,EffectofvorinostatonINK4familyandHDACs1,2,and3inpancreaticcancerandhepatocellularcarcinoma,Researchinpharmaceuticalsciences16(3)(2021)260-268.[6]N.Tanaka,A.A.Patel,L.Tang,etal.,ReplicationStressLeadingtoApoptosiswithintheS-phaseContributestoSynergismbetweenVorinostatandAZD1775inHNSCCHarboring