组蛋白去乙酰化酶抑制剂及其衍生的多靶点抑制剂在胃肠道肿瘤中的研究进展  

Research progress of histone deacetylase inhibitors and their deriving multitarget inhibitors in gastrointestinal cancer

作　　者：李显 丁杰 夏宇[3] 岑祥莹[1] 吴明 张林[1,2] 樊斐 曾家兴 糜睿 LI Xian;DING Jie;XIA Yu;CEN Xiangying;WU Ming;ZHANG Lin;FAN Fei;ZENG Jiaxing;MI Rui(Zunyi Medical University,Zunyi,Guizhou 563003,China;Department of Gastrointestinal Surgery,Guizhou Provincial People’s Hospital,Guiyang 550002,China;Department of Stomatology,Guizhou Provincial People’s Hospital,Guiyang 550002,China;Department of General Surgery,Zhijin County People's Hospital,Bijie,Guizhou,552100,China)

机构地区：[1]遵义医科大学,贵州遵义563003 [2]贵州省人民医院胃肠外科,贵州贵阳550002 [3]贵州省人民医院口腔科,贵州贵阳550002 [4]贵州省织金县人民医院普通外科,贵州毕节552100

出　　处：《中国普通外科杂志》2020年第10期1251-1260,共10页China Journal of General Surgery

基　　金：国家自然科学基金资助项目(81360366,81302169);贵州省社会发展攻关资助项目(黔科合SZ字[2014]3023号);贵州省社会发展攻关资助项目(黔科合LH字[2014]7012号);贵州省优秀青年科技人才培养对象基金资助项目(黔科合平台人才[2017]5602);贵州省高层次创新型人才培养对象资助项目(GZSYQCC[2014]001);贵州省科技计划基金资助项目(黔科合基础[2019]1198号;黔科合基础[2020]1Z064);贵州省高层次留学人才创新创业基金资助项目(留学人才择优资助合同(2018)04号)。

摘　　要：胃癌的新发病例排在恶性肿瘤的第5位,而结直肠癌是世界第三大常见的恶性肿瘤和第四大癌症死亡原因。组蛋白乙酰化的动态平衡由组蛋白乙酰转移酶(HAT)和组蛋白去乙酰化酶(HDAC)两个酶家族共同维持。HDAC能将赖氨酸上的乙酰基去除,从而抑制基因转录,但HDAC异常高表达可诱导正常细胞发生癌变,并参与其发展、增殖、侵袭和转移。靶向抑制HDAC已被证实具有抗肿瘤的效应,组蛋白去乙酰化酶抑制剂(HDACi)能抑制HDAC的表达及活性,并通过影响细胞活性氧水平、阻滞细胞周期、促进损伤DNA修复、抗血管新生、影响细胞信号通路、诱导自噬凋亡及增加细胞对放化疗药物的敏感性发挥强效的抗瘤作用,在胃癌及结直肠癌中HDAC则表达增高,HDACi在胃肠道肿瘤的研究中也呈现出良好的成效,由于I、II和IV类HDAC的催化核心发挥功能均依赖于Zn^2+,故多数HDACi均含有Zn^2+鳌合基团,异羟肟酸类抑制剂中的SAHA、TSA小剂量单独给药时已具有良好的抗肿瘤的成效,但后期临床研究发现,SAHA由于活性低,在治疗胃癌及结直肠癌的临床试验疗效并不佳,TSA的活性有所提高,但对HDAC选择性仍低,苯甲酰胺类HDACi在选择性上得以改善,但也无法只针对于特定亚型的HDAC,后期的环肽类及新报道的HDACi在HDAC的选择性上逐渐增加,但也仅限在动物及细胞实验阶段,并且上述的HDACi除与Zn^2+结合之外还能与其他金属酶结合,从而缺乏绝对的特异性,故大多数的HDACi在很小的剂量下就已引发了副作用,由于肿瘤的发生、发展涉及多环节、多因素,单一靶标常常不能有效杀灭癌细胞,并易产生耐药性,联合多靶标比单一靶标具有更强的抑癌效用,甚至能减轻药物耐药性的产生,但有时联合用药时会因药物间相互影响而带来不良反应,为了避免药物间相互影响,研究者基于药效基团拼接理念,将HDACi活性基团与其他不同�New cases of gastric cancer rank fifth in malignant tumors,while colorectal cancer is the third most common malignant tumor and the fourth most common cause of cancer death in the world.The dynamic balance of histone acetylation is jointly maintained by histone acetyltransferase(HAT)and histone deacetylase,(HDAC)enzyme families.HDAC can remove acetyl groups from lysine,thus inhibiting gene transcription.However,abnormally high expression of HDAC can induce normal cells to turn cancerous and participate in its development,proliferation,invasion and metastasis.Targeted inhibition of HDAC has been proved to have anti-tumor effect.Histone deacetylase inhibitors(HDACi)can inhibit the expression and activity of HDAC.Moreover,HDAC plays a potent anti-tumor role by influencing the level of cell reactive oxygen species,blocking cell cycle,promoting repair of damaged DNA,resisting angiogenesis,influencing cell signal pathways,inducing autophagy apoptosis and increasing the sensitivity of cells to chemoradiotherapy drugs.HDAC expression is increased in gastric cancer and colorectal cancer,and HDACi also shows good results in the study of gastrointestinal tumors.Since the catalytic core functions of class I,II and IV HDAC all depend on Zn^2+,most HDACi contain Zn^2+chelating groups.SAHA and TSA in hydroxamic acid inhibitors have good anti-tumor effects when administered alone in small doses.However,later clinical studies found that SAHA has poor clinical efficacy in treating gastric cancer and colorectal cancer due to its low activity.The activity of TSA has been improved,but its selectivity to HDAC is still low,benzamide HDACi is improved in selectivity,but it cannot be only targeted at specific subtypes of HDAC.The selectivity of late cyclic peptides and newly reported HDACi is gradually increased,but it is only limited to animal and cell experimental stages,and the above-mentioned HDACi can combine with other metalloenzymes in addition to Zn^2+,thus lacking absolute specificity.Therefore,most HDACi has caused side effects

关 键 词：胃肠肿瘤 组蛋白类 组蛋白脱乙酰基酶类 酶抑制剂 综述文献 

分 类 号：R735.2[医药卫生—肿瘤]