組織蛋白去乙醯酶抑制劑

組織蛋白去乙醯酶抑制劑(英語：HDAC inhibitor，簡寫HDI或HDAC抑制劑)是一種透過抑制身體內組織蛋白去乙醯酶功能的藥物類別，亦存在於胎兒及四川胡椒內。現時有健康食品生產商建議透過進食花椒油而達至防癌的功效。

現時醫學界有研究透過「組織蛋白去乙醯酶抑制劑」來治療癌症^[1]及神经退行性疾病(neurodegenerative diseases)。這些抑制劑的具體機制，例如有關的化合物如何達到有關的功效，到現在還未清楚。不過，有關文獻亦有提出可能的表觀遺傳學途徑^[2] Richon et al.^[3]發現HDAC抑制劑可以透過引導p21 (WAF1)來調節P53的腫瘤抑制功能^[4]。對於 HDAC 抑制劑如何調控基因表達，目前已有比較大的進展。持續的研究 HDAC 抑制劑的調節基因機制，將快速促進新藥設計及生物標記的鑑定 ^[5]。

通路

HDAC参与了视网膜母细胞瘤蛋白抑制细胞增殖的通路。pRb蛋白是一个复合物的组成部分，该复合物将HDAC吸引到染色质上以使其去乙酰化组蛋白。^[6] HDAC1通过直接相互作用负调控心血管转录因子Kruppel样因子5。^[7]

雌激素已被确认是一种有丝分裂原，通过与雌激素受体α（ERalpha）结合而参与乳腺癌的肿瘤发生和进展。最新数据表明，由HDAC和DNA甲基化介导的染色质失活是人类乳腺癌细胞中ERalpha沉默的关键组成部分。^[8]

HDAC抑制剂也与某些基因启动子的抑制有关。然而，这可能是由于其他负调控蛋白活性的增加所致。例如包括SAHA（英语：SAHA）, LAQ824/LBH589, CI994, MS275（英语：MS275）和莫塞替诺特。^[9]

药用HDI

不少已经在使用的药物被发现同时具有抑制第I、II、IV类HDAC的功能，都是靠和锌原子结合起效。2005年已有的化学结构种类按照结合强度递减，有：^[10]

异羟肟酸类（或羟胺酯类），例如曲古抑菌素A（英语：trichostatin A），
环状四肽（英语：tetrapeptide）类（如曲泊肽B），以及环肽类，如罗米地辛（英语：romidepsin）、波可地辛
苯胺类，
亲电子酮类，以及
脂肪酸类化合物，如丙戊酸、苯丁酸钠（英语：Sodium phenylbutyrate）。

2007年新开发出的种类有：

异羟肟酸 : trichostatin A（英语：trichostatin A）, 伏立诺他 (SAHA), belinostat（英语：belinostat） (PXD101), resminostat（英语：resminostat）, 艾贝司他, givinostat（英语：givinostat）, LAQ824, ivaltinostat, nanatinostat and panobinostat（英语：panobinostat） (LBH589)
苯甲酰胺 : entinostat（英语：entinostat） (MS-275), tacedinaline (CI994), zabadinostat（英语：zabadinostat）, and 莫塞替诺特 (MGCD0103).^[11]^[12]

第三类HDAC即Sirtuin（英语：Sirtuin）基于NAD+工作，可被细胞内的烟酰胺抑制。^[13]

參考

^ Marks PA, Dokmanovic M. Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert opinion on investigational drugs. 2005, 14 (12): 1497–511. PMID 16307490. doi:10.1517/13543784.14.12.1497.
^ Claude Monneret. Histone deacetylase inhibitors for epigenetic therapy of cancer. Anticancer Drugs. April 2007, 18: 363–70.
^ Richon VM, Sandhoff TW, Rifkind RA, Marks PA. AUG 29 2000. "Histone deacetylase inhibitor selectively induces p21(WAF1) expression and gene-associated histone acetylation." [[美国国家科学院院刊|]] 97(18):10014-10019.
^ el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. NOV 19 1993. "WAF1, a potential mediator of p53 tumor suppression." Cell 75(4):817-25.
^ Chueh, Anderly C.; Tse, Janson W.T.; Tögel, Lars; Mariadason, John M. Mechanisms of Histone Deacetylase Inhibitor-Regulated Gene Expression in Cancer Cells. Antioxidants & Redox Signaling. 2014-02-10, 23 (1): 66–84. ISSN 1523-0864. PMC 4492771 . PMID 24512308. doi:10.1089/ars.2014.5863.
^ Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. 1998 Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391(6667):597-601.
^ Matsumura T, Suzuki T, Aizawa K, Munemasa Y, Muto S, Horikoshi M, Nagai R 2005 The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.J Bio Chem(journal)J Bio Chem 280(13):12123-9
^ Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y, Mita K, Hamaguchi M, Hara Y, Kobayashi S, Iwase H Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast.2005 Breast Cancer Res Treat（英语：Breast Cancer Res Treat）Nov;94(1):11-6.
^ Beckers T, Burkhardt C, Wieland H; et al. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int. J. Cancer. 2007, 121 (5): 1138–48. PMID 17455259. doi:10.1002/ijc.22751.
^ Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Annual Review of Pharmacology and Toxicology. 2005, 45: 495–528. PMID 15822187. doi:10.1146/annurev.pharmtox.45.120403.095825.
^ Beckers T, Burkhardt C, Wieland H, Gimmnich P, Ciossek T, Maier T, Sanders K. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. International Journal of Cancer. September 2007, 121 (5): 1138–48. PMID 17455259. doi:10.1002/ijc.22751 .
^ Acharya MR, Sparreboom A, Venitz J, Figg WD. Rational development of histone deacetylase inhibitors as anticancer agents: a review. Molecular Pharmacology. October 2005, 68 (4): 917–32. PMID 15955865. S2CID 1439957. doi:10.1124/mol.105.014167.
^ Porcu M, Chiarugi A. The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Trends in Pharmacological Sciences. February 2005, 26 (2): 94–103. PMID 15681027. doi:10.1016/j.tips.2004.12.009.

[1] Marks PA, Dokmanovic M. Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert opinion on investigational drugs. 2005, 14 (12): 1497–511. PMID 16307490. doi:10.1517/13543784.14.12.1497.

[2] Claude Monneret. Histone deacetylase inhibitors for epigenetic therapy of cancer. Anticancer Drugs. April 2007, 18: 363–70.

[Richon-3] Richon VM, Sandhoff TW, Rifkind RA, Marks PA. AUG 29 2000. "Histone deacetylase inhibitor selectively induces p21(WAF1) expression and gene-associated histone acetylation." [[美国国家科学院院刊|]] 97(18):10014-10019.

[el-Deiry-4] -Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. NOV 19 1993. "WAF1, a potential mediator of p53 tumor suppression." Cell 75(4):817-25.

[5] Chueh, Anderly C.; Tse, Janson W.T.; Tögel, Lars; Mariadason, John M. Mechanisms of Histone Deacetylase Inhibitor-Regulated Gene Expression in Cancer Cells. Antioxidants & Redox Signaling. 2014-02-10, 23 (1): 66–84. ISSN 1523-0864. PMC 4492771 . PMID 24512308. doi:10.1089/ars.2014.5863.

[Brehm-6] Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. 1998 Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391(6667):597-601.

[Matsumura-7] Matsumura T, Suzuki T, Aizawa K, Munemasa Y, Muto S, Horikoshi M, Nagai R 2005 The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.J Bio Chem(journal)J Bio Chem 280(13):12123-9

[zhang-8] Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y, Mita K, Hamaguchi M, Hara Y, Kobayashi S, Iwase H Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast.2005 Breast Cancer Res Treat（英语：Breast Cancer Res Treat）Nov;94(1):11-6.

[9] Beckers T, Burkhardt C, Wieland H; et al. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int. J. Cancer. 2007, 121 (5): 1138–48. PMID 17455259. doi:10.1002/ijc.22751.

[Drummond05-10] Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Annual Review of Pharmacology and Toxicology. 2005, 45: 495–528. PMID 15822187. doi:10.1146/annurev.pharmtox.45.120403.095825.

[11] Beckers T, Burkhardt C, Wieland H, Gimmnich P, Ciossek T, Maier T, Sanders K. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. International Journal of Cancer. September 2007, 121 (5): 1138–48. PMID 17455259. doi:10.1002/ijc.22751 .

[pmid15955865-12] Acharya MR, Sparreboom A, Venitz J, Figg WD. Rational development of histone deacetylase inhibitors as anticancer agents: a review. Molecular Pharmacology. October 2005, 68 (4): 917–32. PMID 15955865. S2CID 1439957. doi:10.1124/mol.105.014167.

[13] Porcu M, Chiarugi A. The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Trends in Pharmacological Sciences. February 2005, 26 (2): 94–103. PMID 15681027. doi:10.1016/j.tips.2004.12.009.

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