AbMole小课堂 Chloroquine：溶酶体自噬调控的“枢纽”

AbMole小课堂|Chloroquine：溶酶体/自噬调控的“枢纽”Chloroquine（氯喹，CQ，AbMole，M9559）是一种具有多种生物活性的小分子，早期研究聚焦于其对疟原虫生命周期的干预作用，后续研究逐渐揭示了Chloroquine在细胞生理、免疫调控及病毒-宿主相互作用中的多靶点效应。一、Chloroquine（氯喹，CQ）的作用机理1.Chloroquine（氯喹，CQ）对胞内体/溶酶体的酸性环境的抑制胞内体主要参与细胞内吞物质的运输，它通过V-ATP酶主动泵入质子（H+）维持酸性环境（早期胞内体pH≈6.0，晚期≈5.0）。溶酶体则是一种含多种酸性水解酶（如蛋白酶、核酸酶等）的细胞器，它依赖强酸性环境（pH≈4.5–5.0）发挥降解功能（如降解病原体、衰老细胞器）。Chloroquine（氯喹，AbMole，M9559）巧妙的分子结构使得它在胞外环境中呈脂溶性状态，可自由穿过细胞膜进入细胞。一旦Chloroquine进入胞内体或者溶酶体中，酸性环境中会使其质子化（形成阳离子），此时无法跨膜扩散进入细胞质中，导致在上述酸性细胞器内的被动积累。Chloroquine（氯喹）的积累会不断地结合质子（H+），抑制胞内体/溶酶体的酸性环境。Chloroquine（氯喹，CQ）抑制自噬Chloroquine（氯喹，AbMole，M9559）还是一种经典的自噬抑制剂，在自噬的晚期阶段，自噬小体与溶酶体形成自噬体，以实现受损细胞器、蛋白、核酸等生物大分子的降解。如前所述，Chloroquine可以抑制溶酶体的pH，进而抑制自噬体的降解能力。另外一方面，Chloroquine还能插入脂质双层，改变膜流动性，进而影响自噬小体和溶酶体的融合（图1）。图SEQ图\*ARABIC1.Chloroquineandhydroxychloroquineinautophagy-relatedmechanismsADDINEN.CITE<EndNote><Cite><Author>Ferreira</Author><Year>2021</Year><RecNum>163</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>163</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1750408741">163</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ferreira,PauloMichelPinheiro</author><author>Sousa,RayranWalterRamosde</author><author>Ferreira,JoséRobertodeOliveira</author><author>Militão,GardeniaCarmenGadelha</author><author>Bezerra,DanielPereira</author></authors></contributors><titles><title>Chloroquineandhydroxychloroquineinantitumortherapiesbasedonautophagy-relatedmechanisms</title><secondary-title>PharmacologicalResearch</secondary-title></titles><periodical><full-title>PharmacologicalResearch</full-title></periodical><pages>105582</pages><volume>168</volume><keywords><keyword>Celldeath</keyword><keyword>Chemoresistance</keyword><keyword>Immunomodulatoryproperties</keyword><keyword>Clinicaloption</keyword></keywords><dates><year>2021</year><pub-dates><date>2021/06/01/</date></pub-dates></dates><isbn>1043-6618</isbn><urls><related-urls><url>/science/article/pii/S1043661821001663</url></related-urls></urls><electronic-resource-num>/10.1016/j.phrs.2021.105582</electronic-resource-num></record></Cite></EndNote>[1]Chloroquine（氯喹，CQ）的研究应用Chloroquine（氯喹，CQ）用于自噬研究作为一款经典的晚期自噬抑制剂，Chloroquine（氯喹，AbMole，M9559）可使LC3-II（自噬标志物）无法被溶酶体降解，表现为细胞内LC3-II蛋白水平升高。通过Chloroquine抑制自噬降解，可以观察其对细胞存活、凋亡、代谢等的影响，判断某一表型或者细胞行为是否依赖细胞自噬。Chloroquine（氯喹，CQ）用于肿瘤研究Chloroquine被发现能够抑制肿瘤细胞的增殖，Chloroquine（氯喹，AbMole，M9559）可诱导野生型胶质瘤细胞caspase-3的激活和细胞凋亡的启动。相较于单一使用，Chloroquine更多被用于和其它抑制剂的联用，以增加肿瘤细胞对相关抑制剂的敏感性，产生“1+1＞2”的效果。例如，在急性髓系白血病（AML）细胞系MV-4-11和THP-1的研究中，Chloroquine与阿糖胞苷（Ara-C）、柔红霉素（daunorubicin）和伊达比星（idarubicin）联合使用，显著增强了这些抑制剂的抗肿瘤效果，Chloroquine发挥上述功能的机理主要是通过抑制自噬，降低了细胞的“解毒”能力。Chloroquine（氯喹，CQ）用于病毒研究Chloroquine（氯喹，AbMole，M9559）在体外实验中显示出对多种病毒的抑制作用，包括HIV、SARS-CoV、MERS-CoV和EbolavirusADDINEN.CITE<EndNote><Cite><Author>Mo</Author><Year>2020</Year><RecNum>159</RecNum><DisplayText><styleface="superscript">[2]</style></DisplayText><record><rec-number>159</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1750405726">159</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mo,L.</author><author>Zheng,P.</author></authors></contributors><auth-address>DepartmentofPharmacy,NanfangHospital,SouthernMedicalUniversity,Guangzhou510515,China.</auth-address><titles><title>[Chloroquinephosphate:therapeuticdrugforCOVID-19]</title><secondary-title>NanFangYiKeDaXueXueBao</secondary-title></titles><periodical><full-title>NanFangYiKeDaXueXueBao</full-title></periodical><pages>586-594</pages><volume>40</volume><number>4</number><keywords><keyword>AntiviralAgents</keyword><keyword>Betacoronavirus/*drugeffects</keyword><keyword>Covid-19</keyword><keyword>China</keyword><keyword>Chloroquine/*analogs&derivatives/therapeuticuse</keyword><keyword>*CoronavirusInfections/drugtherapy</keyword><keyword>Humans</keyword><keyword>*Pandemics</keyword><keyword>*Pneumonia,Viral/drugtherapy</keyword><keyword>SARS-CoV-2</keyword><keyword>COVID-19DrugTreatment</keyword><keyword>antiviral</keyword><keyword>chloroquinephosphate</keyword><keyword>coronavirusdisease2019</keyword><keyword>pharmacokinetics</keyword><keyword>safety</keyword></keywords><dates><year>2020</year><pub-dates><date>Apr30</date></pub-dates></dates><isbn>1673-4254(Print) 1673-4254</isbn><accession-num>32895128</accession-num><urls></urls><custom2>PMC7225120</custom2><electronic-resource-num>10.12122/j.issn.1673-4254.2020.04.22</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>chi</language></record></Cite></EndNote>[2]。Chloroquine能够改变细胞内pH值，从而干扰病毒的复制过程。此外，它还可能通过抑制病毒进入宿主细胞、阻断病毒与宿主细胞受体的结合以及抑制病毒的组装和释放来发挥作用ADDINEN.CITEADDINEN.CITE.DATA[3]。Chloroquine（氯喹，CQ）用于自身免疫疾病研究近些年，Chloroquine（氯喹，AbMole，M9559）也是自身免疫性疾病研究领域的明星分子。Chloroquine及其衍生物羟氯喹（Hydroxychloroquine）被广泛用于研究系统性红斑狼疮（SLE）和类风湿性关节炎（RA）等自身免疫性疾病。Chloroquine的机制包括抑制抗原呈递细胞的功能，减少炎症细胞因子的产生，以及调节T细胞和B细胞的活化。这些作用有助于减轻自身免疫性疾病的炎症反应ADDINEN.CITE<EndNote><Cite><Author>Al-Hamadani</Author><Year>2025</Year><RecNum>160</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>160</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1750407618">160</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Al-Hamadani,M.</author><author>Darweesh,M.</author><author>Mohammadi,S.</author><author>Al-Harrasi,A.</author></authors></contributors><auth-address>NaturalandMedicalSciencesResearchCenter,UniversityofNizwa,Nizwa616,AdDakhiliyah,Oman. NaturalandMedicalSciencesResearchCenter,UniversityofNizwa,Nizwa616,AdDakhiliyah,Oman.s.mohammadi@.om.</auth-address><titles><title>Chloroquineandhydroxychloroquine:Immunomodulatoryeffectsinautoimmunediseases</title><secondary-title>WorldJBiolChem</secondary-title></titles><periodical><full-title>WorldJBiolChem</full-title></periodical><pages>107042</pages><volume>16</volume><number>2</number><keywords><keyword>Autoimmunediseases</keyword><keyword>Autophagy</keyword><keyword>Chloroquine</keyword><keyword>Hydroxychloroquine</keyword><keyword>Immunomodulation</keyword><keyword>Toll-likereceptor</keyword></keywords><dates><year>2025</year><pub-dates><date>Jun5</date></pub-dates></dates><isbn>1949-8454(Print) 1949-8454(Electronic) 1949-8454(Linking)</isbn><accession-num>40476257</accession-num><urls><related-urls><url>/pubmed/40476257</url></related-urls></urls><custom1>Conflict-of-intereststatement:Alltheauthorsdeclarethattherearenoconflictsofinteresttodisclose.</custom1><custom2>PMC12136085</custom2><electronic-resource-num>10.4331/wjbc.v16.i2.107042</electronic-resource-num></record></Cite></EndNote>[4]。图SEQ图\*ARABIC2.Chloroquine抑制自身免疫疾病的原理ADDINEN.CITE<EndNote><Cite><Author>Al-Hamadani</Author><Year>2025</Year><RecNum>160</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>160</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1750407618">160</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Al-Hamadani,M.</author><author>Darweesh,M.</author><author>Mohammadi,S.</author><author>Al-Harrasi,A.</author></authors></contributors><auth-address>NaturalandMedicalSciencesResearchCenter,UniversityofNizwa,Nizwa616,AdDakhiliyah,Oman. NaturalandMedicalSciencesResearchCenter,UniversityofNizwa,Nizwa616,AdDakhiliyah,Oman.s.mohammadi@.om.</auth-address><titles><title>Chloroquineandhydroxychloroquine:Immunomodulatoryeffectsinautoimmunediseases</title><secondary-title>WorldJBiolChem</secondary-title></titles><periodical><full-title>WorldJBiolChem</full-title></periodical><pages>107042</pages><volume>16</volume><number>2</number><keywords><keyword>Autoimmunediseases</keyword><keyword>Autophagy</keyword><keyword>Chloroquine</keyword><keyword>Hydroxychloroquine</keyword><keyword>Immunomodulation</keyword><keyword>Toll-likereceptor</keyword></keywords><dates><year>2025</year><pub-dates><date>Jun5</date></pub-dates></dates><isbn>1949-8454(Print) 1949-8454(Electronic) 1949-8454(Linking)</isbn><accession-num>40476257</accession-num><urls><related-urls><url>/pubmed/40476257</url></related-urls></urls><custom1>Conflict-of-intereststatement:Alltheauthorsdeclarethattherearenoconflictsofinteresttodisclose.</custom1><custom2>PMC12136085</custom2><electronic-resource-num>10.4331/wjbc.v16.i2.107042</electronic-resource-num></record></Cite></EndNote>[4]范例详解Autophagy.2024Oct;20(10):2255-2274四川大学、中山大学附属第八医院的科研人员在上述文章中，发现了一种新的lncRNA，即lnc-HZ12，它在早期胚胎丢失组中存在异常高表达的现象。Lnc-HZ12抑制BBC3伴侣介导的自噬（CMA）降解，促进滋养层细胞凋亡。在探究lnc-HZ12对BBC3的调控机制实验中，研究人员使用来自AbMole的MG132（AbMole，M1902）、Chloroquine（CQ，AbMole，M9559）、Ammoniumchloride（AbMole，M9929）处理lnc-HZ12过表达或沉默的Swan71细胞，最终成功证明了lnc-HZ12通过自噬-溶酶体途径降解BBC3蛋白。图SEQ图\*ARABIC3.Lnc-HZ12suppressedCMAdegradationofBBC3ADDINEN.CITEADDINEN.CITE.DATA[5].AdvSci(Weinh).2021Jan6;8(4):2003205.中国科学院苏州生物医学工程技术研究所、南京师范大学的实验人员在上述论文中探索了PRKD3（ProteinKinaseD3）在TNBC（三阴性乳腺癌）中对CLU（一种应激激活的分子伴侣）的调控作用及其在肿瘤生长中的作用机制。在实验中，科研人员使用了AbMole提供的蛋白酶体抑制剂MG132（AbMole，M1902）和溶酶体抑制剂Chloroquine（CQ，AbMole，M9559）处理TNBC细胞，发现CQ能够显著恢复PRKD3缺失导致的CLU降解，而MG132无此效果，表明PRKD3通过抑制CLU的溶酶体降解来稳定CLU蛋白ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2021</Year><RecNum>162</RecNum><DisplayText><styleface="superscript">[6]</style></DisplayText><record><rec-number>162</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1750408576">162</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,Y.</author><author>Zhou,Y.</author><author>Ma,X.</author><author>Chen,L.</author></authors></contributors><auth-address>TheKeyLaboratoryofBio-MedicalDiagnosticsSuzhouInstituteofBiomedicalEngineeringandTechnologyChineseAcademyofSciencesSuzhou215163P.R.China. CancerInstituteDepartmentofBiochemistryJiangsuKeyLaboratoryforMolecularandMedicalBiotechnologyCollegeofLifeScienceNanjingNormalUniversityNanjing210023P.R.China. TheFirstAffiliatedHospitalofSoochowUniversitySoochowUniversitySuzhou215006P.R.China.</auth-address><titles><title>InhibitionLysosomalDegradationofClusterinbyProteinKinaseD3PromotesTriple-NegativeBreastCancerTumorGrowth</title><secondary-title>AdvSci(Weinh)</secondary-title></titles><periodical><full-title>AdvSci(Weinh)</full-title></periodical><pages>2003205</pages><volume>8</volume><number>4</number><edition>20210106</edition><keywords><keyword>clusterin</keyword><keyword>proteinkinaseD3</keyword><keyword>targetedtherapies</keyword><keyword>triple‐negativebreastcancer</keyword><keyword>tumorgrowth</keyword></keywords><dates><year>2021</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>2198-3844(Print) 2198-3844</isbn><accession-num>33643800</accession-num><urls></urls><custom1>NanjingNormalUniversityhasfiledpatentapplicationsrelatedtothiswork,listingL.C.,Y.L.,andJ.Z.asinventors.</custom1><custom2>PMC7887572</custom2><electronic-resource-num>10.1002/advs.202003205</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[6]。图SEQ图\*ARABIC4.PRKD3inhibitsdegradationofCLUviainhibitinglysosomalpathwaynotproteasomalpathwayADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2021</Year><RecNum>162</RecNum><DisplayText><styleface="superscript">[6]</style></DisplayText><record><rec-number>162</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1750408576">162</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,Y.</author><author>Zhou,Y.</author><author>Ma,X.</author><author>Chen,L.</author></authors></contributors><auth-address>TheKeyLaboratoryofBio-MedicalDiagnosticsSuzhouInstituteofBiomedicalEngineeringandTechnologyChineseAcademyofSciencesSuzhou215163P.R.China. CancerInstituteDepartmentofBiochemistryJiangsuKeyLaboratoryforMolecularandMedicalBiotechnologyCollegeofLifeScienceNanjingNormalUniversityNanjing210023P.R.China. TheFirstAffiliatedHospitalofSoochowUniversitySoochowUniversitySuzhou215006P.R.China.</auth-address><titles><title>InhibitionLysosomalDegradationofClusterinbyProteinKinaseD3PromotesTriple-NegativeBreastCancerTumorGrowth</title><secondary-title>AdvSci(Weinh)</secondary-title></titles><periodical><full-title>AdvSci(Weinh)</full-title></periodical><pages>2003205</pages><volume>8</volume><number>4</number><edition>20210106</edition><keywords><keyword>clusterin</keyword><keyword>proteinkinaseD3</keyword><keyword>targetedtherapies</keyword><keyword>triple‐negativebreastcancer</keyword><keyword>tumorgrowth</keyword></keywords><dates><year>2021</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>2198-3844(Print) 2198-3844</isbn><accession-num>33643800</accession-num><urls></urls><custom1>NanjingNormalUniversityhasfiledpatentapplicationsrelatedtothiswork,listin