GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions.
GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions.
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GNS561是一种临床阶段的PPT1抑制剂，通过调节溶酶体功能对肝细胞癌有效。
DOI：
10.1080/15548627.2021.1988357
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发表时间：
2022-03
期刊：
影响因子：
13.3
通讯作者：
Halfon, Philippe
中科院分区：
文献类型：
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作者：
Brun, Sonia;Bestion, Eloine;Raymond, Eric;Bassissi, Firas;Jilkova, Zuzana Macek;Mezouar, Soraya;Rachid, Madani;Novello, Marie;Tracz, Jennifer;Hamai, Ahmed;Lalmanach, Gilles;Vanderlynden, Lise;Legouffe, Raphael;Stauber, Jonathan;Schubert, Thomas;Plach, Maximilian G.;Courcambeck, Jerome;Drouot, Cyrille;Jacquemot, Guillaume;Serdjebi, Cindy;Roth, Gael;Baudoin, Jean-Pierre;Ansaldi, Christelle;Decaens, Thomas;Halfon, Philippe
肝细胞癌是最常见的原发性肝癌。巨噬/自噬抑制剂已经在癌症中得到了广泛的研究，但迄今为止，尚未在临床试验中达到疗效。在这项研究中，我们证明了GNS561，一种新的自噬抑制剂，其抗癌活性先前与溶酶体细胞死亡有关，在一组人类癌细胞系和两种肝细胞癌的体内模型中显示出高的肝脏趋向性和有效的抗肿瘤活性。我们发现，由于其溶酶体性，GNS561可以到达并特异性抑制其酶靶点PPT1（棕榈酰蛋白硫酯酶1），导致溶酶体未结合的Zn2+积累，组织蛋白酶活性受损，自噬通量受阻，MTOR（雷帕霉素激酶的机制靶点）位置改变，溶酶体膜渗透，caspase激活和细胞死亡。因此，刚刚成功完成肝癌全球1b期临床试验的GNS561，代表了一种很有前景的候选新药和一种有希望的癌症治疗策略。缩写：ANXA5：膜联蛋白A5；ATCC：美式文化收藏；BafA1：巴霉素A1；牛血清白蛋白；CASP3: caspase 3；CASP7: caspase 7；CASP8: caspase 8；CCND1: cyclin D1；CTSB：组织蛋白酶B；CTSD：组织蛋白酶D；CTSL：组织蛋白酶L；CQ:氯喹;iCCA：肝内胆管癌；窝:diethylnitrosamine;DMEM: Dulbelcco改良Eagle培养基；胎牛血清；FITC：异硫氰酸荧光素；GAPDH：甘油醛-3-磷酸脱氢酶；HCC：肝细胞癌；HCQ:羟氯喹;HDSF: hexadecylsulfonylfluoride;IC50：平均半最大抑制浓度；LAMP：溶酶体相关膜蛋白；LC3-II：磷脂酰乙醇胺偶联形式的MAP1LC3；LMP：溶酶体膜渗透；MALDI：基质辅助激光解吸电离；MAP1LC3/LC3：微管相关蛋白1轻链3；MKI67：增殖标志物Ki-67；MTOR：雷帕霉素激酶的机制靶点MRI：磁共振成像；NH4Cl：氯化铵；NtBuHA: N-tert-butylhydroxylamine;PARP：聚adp核糖聚合酶；PBS：磷酸盐缓冲盐水；PPT1：棕榈酰蛋白硫酯酶1；SD：标准差；SEM：标准误差均值；和,与;Zn2+：锌离子；Z-Phe: Z-Phe-Tyt (tBu) -diazomethylketone;Z-VAD-FMK: carbobenzoxy-valyl-alanyl-天冬氨酸-[o -甲基]-氟甲基酮。
Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment. Abbreviations: ANXA5:annexin A5; ATCC: American type culture collection; BafA1: bafilomycin A1; BSA: bovine serum albumin; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CCND1: cyclin D1; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; CQ: chloroquine; iCCA: intrahepatic cholangiocarcinoma; DEN: diethylnitrosamine; DMEM: Dulbelcco’s modified Eagle medium; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; HDSF: hexadecylsulfonylfluoride; IC50: mean half-maximal inhibitory concentration; LAMP: lysosomal associated membrane protein; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3; LMP: lysosomal membrane permeabilization; MALDI: matrix assisted laser desorption ionization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; MRI: magnetic resonance imaging; NH4Cl: ammonium chloride; NtBuHA: N-tert-butylhydroxylamine; PARP: poly(ADP-ribose) polymerase; PBS: phosphate-buffered saline; PPT1: palmitoyl-protein thioesterase 1; SD: standard deviation; SEM: standard error mean; vs, versus; Zn2+: zinc ion; Z-Phe: Z-Phe-Tyt(tBu)-diazomethylketone; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone.
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影响因子：
--
作者：
Jilkova ZM;Kuyucu AZ;Kurma K;Ahmad Pour ST;Roth GS;Abbadessa G;Yu Y;Schwartz B;Sturm N;Marche PN;Hainaut P;Decaens T
通讯作者：
Decaens T
影响因子：
28.2
作者：
Klempner SJ;Myers AP;Cantley LC
通讯作者：
Cantley LC
DOI：
10.1111/j.1600-0773.1997.tb00285.x
发表时间：
1997-02-01
期刊：
PHARMACOLOGY & TOXICOLOGY
影响因子：
--
作者：
Daniel, WA;Wojcikowski, J
通讯作者：
Wojcikowski, J
影响因子：
4.7
作者：
Harder BG;Blomquist MR;Wang J;Kim AJ;Woodworth GF;Winkles JA;Loftus JC;Tran NL
通讯作者：
Tran NL
影响因子：
28.2
作者：
Rebecca, Vito W.;Nicastri, Michael C.;Amaravadi, Ravi K.
通讯作者：
Amaravadi, Ravi K.