乙酰肝素酶靶点药物的抗肿瘤活性研究进展

摘要/Abstract

摘要： 乙酰肝素酶是葡萄糖醛酸内切酶,通过水解细胞膜和细胞外基质的重要组成成分-硫酸乙酰肝素,释放出促生长因子,有利于肿瘤细胞的侵袭和转移。以乙酰肝素酶作为抗癌药物靶点的一系列半合成多糖类、合成小分子类和天然产物类化合物陆续被发现出来,其PI-88已经进入临床研究阶段。另外乙酰肝素酶的晶体结构也已经成功得到解析,使基于蛋白结构的理性药物设计成为可能。本文系统的介绍了乙酰肝素酶抑制剂抗肿瘤活性研究进展。

关键词: 乙酰肝素酶, 蛋白结构, 抑制剂, 抗肿瘤活性

Abstract: Heparanase is a glucuronic acid enzyme, it hydrolizes heparin sulfate, which is main components of cell membrane and extracellular matrix, growth factors are released to promote tumor cell invasion and metastasis. As for the antineoplastic drug targets, a series of polysaccharides, synthetic small chemical compounds and natural product compounds have been found, some of them have begin the clinical research. The crystal structures of heparanase have successfully been discovered, so it is possible to do rational drug design based on 3D protein structures. This paper introduces antineoplastic activity research advance of heparanase inhibitors in details.

Key words: heparanase, protein structure, inhibitor, antineoplastic activity

中图分类号:

张军, 崔亚放, 张昌卓, 张亚, 邵鹏. 乙酰肝素酶靶点药物的抗肿瘤活性研究进展[J]. 中国临床药理学与治疗学, 2014, 19(8): 953-960.

ZHANG Jun, CUI Ya-fang, ZHANG Chang-zhuo, ZHANG Ya, SHAO Peng. Advancement of antineoplastic activity research on heparanase drugs[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(8): 953-960.

参考文献 34

[1]	Lindahl U.Biosynthesis of heparin[J]. Biochem Soc Trans, 1990, 18(5): 803-805.
[2]	Vlodavsky I, Beckhove P, Lerner I, et al.Significance of heparanase in cancer and inflammation[J]. Cancer Microenviron, 2012, 5(2): 115-132.
[3]	李燕杰, 彭清忠. 乙酰肝素酶的结构、功能及调控[J]. 生物技术通讯, 2003, 14(2): 141-144.
[4]	Han YH, Garron ML, Kim HY, et al.Structural snapshots of heparin depolymerization by heparin lyase I[J]. J Biol Chem, 2009, 284(49): 34019-34027.
[5]	Shaya D, Tocilj A, Li Y, et al.Crystal structure of heparinase II from Pedobacter heparinus and its complex with a disaccharide product[J]. J Biol Chem, 2006, 281(22): 15525-15535.
[6]	Shaya D, Zhao W, Garron ML, et al.Catalytic mechanism of heparinase II investigated by site-directed mutagenesis and the crystal structure with its substrate[J]. J Biol Chem, 2010, 285(26): 20051-20061.
[7]	Dong W, Lu W, McKeehan WL, et al. Structural basis of heparan sulfate-specific degradation by heparinase III[J]. Protein Cell, 2012, 3(12): 950-961.
[8]	Vlodavsky I, Friedmann Y, Elkin M, et al.Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis(J]. Nat Med, 1999, 5(7): 793-802.
[9]	Zcharia E, Metzger S, Chajek-Shaul T, et al.Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis[J]. J Mammary Gland Biol Neoplasia, 2001, 6(3): 311-322.
[10]	Ikeguchi M, Hirooka Y, Kaibara N.Heparanase gene expression and its correlation with spontaneous apoptosis in hepatocytes of cirrhotic liver and carcinoma[J]. Eur J Cancer, 2003, 39(1): 86-90.
[11]	陈晓鹏,刘颖斌,史良会,等. 肝素对肝癌细胞乙酰肝素酶mRNA表达和侵袭能力的影响[J]. 中国临床药理学与治疗学, 2006, 11(7): 810-813.
[12]	Zeng C, Ke ZF, Luo WR, et al.Heparanase overexpression participates in tumor growth of cervical cancer in vitro and in vivo[J]. Med Oncol, 2013, 30(1): 403.
[13]	Chen Z, Zhu L, Li X, et al.Down-regulation of heparanase leads to the inhibition of invasion and proliferation of A549 cells in vitro and in vivo[J]. Acta Biochim Biophys Sin (Shanghai), 2013, 45(3): 188-193.
[14]	Valerio S, Pastore A, Adinolfi M, et al.Sequential one-pot glycosidations catalytically promoted: unprecedented strategy in oligosaccharide synthesis for the straightforward assemblage of the antitumor PI-88 pentasaccharide[J]. J Org Chem, 2008, 73(12): 4496-503.
[15]	Karoli T, Liu L, Fairweather JK, et al.Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88)[J]. J Med Chem, 2005, 48(26): 8229-8236.
[16]	Johnstone KD, Karoli T, Liu L, et al.Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth[J]. J Med Chem, 2010, 53(4): 1686-1699.
[17]	Liang XJ, Yuan L, Hu J, et al.Phosphomannopentaose sulfate (PI-88) suppresses angiogenesis by downregulating heparanase and vascular endothelial growth factor in an oxygen-induced retinal neovascularization animal model[J]. Mol Vis, 2012, 18: 1649-1657.
[18]	Ma P, Luo Y, Zhu X,et al.Phosphomannopentaose sulfate (PI-88) inhibits retinal leukostasis in diabetic rat[J]. Biochem Biophys Res Commun, 2009, 380(2): 402-406.
[19]	Chow LQ, Gustafson DL, O'Bryant CL, et al. A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies[J]. Cancer Chemother Pharmacol, 2008, 63(1): 65-74.
[20]	Khasraw M, Pavlakis N, McCowatt S, et al. Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer[J]. Ann Oncol, 2010, 21(6): 1302-1307.
[21]	Liu CJ, Lee PH, Lin DY, et al.Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage[J]. J Hepatol, 2009, 50(5): 958-968.
[22]	Ferro V, Liu L, Johnstone KD, et al.Discovery of PG545: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis[J]. J Med Chem, 2012, 55(8): 3804-3813.
[23]	Dredge K, Hammond E, Handley P, et al.PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models[J]. Br J Cancer, 2011, 104(4): 635-642.
[24]	Hammond E, Brandt R, Dredge K.PG545, a Heparan Sulfate Mimetic, Reduces Heparanase Expression In Vivo, Blocks Spontaneous Metastases and Enhances Overall Survival in the 4T1 Breast Carcinoma Model[J]. PLoS One, 2012, 7(12): 1-11.
[25]	Borsig L, Vlodavsky I, Ishai-Michaeli R, et al.Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase[J]. Neoplasia, 2011, 13(5): 445-452.
[26]	Chen HM, Gao Y, Yan XJ.Carrageenan oligosaccharides inhibit growth-factor binding and heparanase activity[J]. Yao Xue Xue Bao, 2011, 46(3): 280-284.
[27]	Courtney SM, Hay PA, Buck RT, et al.2,3-Dihydro-1,3-dioxo-1H-isoindole-5- carboxylic acid derivatives: a novel class of small molecule heparanase inhibitors[J]. Bioorg Med Chem Lett, 2004, 14(12): 3269-3273.
[28]	Courtney SM, Hay PA, Buck RT, et al.Furanyl-1,3-thiazol-2-yl and benzoxazol- 5-yl acetic acid derivatives: novel classes of heparanase inhibitor[J]. Bioorg Med Chem Lett, 2005, 15(9): 2295-2299.
[29]	Basappa, Murugan S, Kavitha CV, et al. A small oxazine compound as an anti-tumor agent: a novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-α[J]. Cancer Lett, 2010, 297(2): 231-243.
[30]	Pan W, Miao HQ, Xu YJ, et al.1-[4-(1H-Benzoimidazol-2-yl)-phenyl]-3- [4- (1H-benzoimidazol-2-yl)-phenyl]-urea derivatives as small molecule heparanase inhibitors[J]. Bioorg Med Chem Lett, 2006, 16(2): 409-412.
[31]	Shiozawa H, Takahashi M, Takatsu T, et al.Trachyspic acid, a new metabolite produced by Talaromyces trachyspermus, that inhibits tumor cell heparanase: taxonomy of the producing strain, fermentation, isolation, structural elucidation, and biological activity[J]. J Antibiot (Tokyo), 1995, 48(5): 357-362.
[32]	Hirai K, Ooi H, Esumi T, et al.Total synthesis of (+/-)-trachyspic acid and determination of the relative configuration[J]. Org Lett, 2003, 5(6): 857-859.
[33]	Kwon HS, Park YM, Lee HJ, et al.Prevalence and clinical characteristics of the metabolic syndrome in middle-aged Korean adults[J]. Korean J Intern Med, 2005, 20(4): 310-316.
[34]	Wang P, Zhang Z, Yu B.Total synthesis of CRM646-A and -B, two fungal glucuronides with potent heparinase inhibition activities[J]. J Org Chem, 2005, 70(22): 8884-8889.