β-异硫氰酸苯乙酯多靶向抗肿瘤作用机制研究进展

摘要/Abstract

摘要： 全球癌症的发病率逐年攀升,癌症治疗已成为科学界和医学界的重要研究课题。β-异硫氰酸苯乙酯(phenethyl isothiocyanate, PEITC)来源于十字花科植物,是广泛被研究的异硫氰酸酯(isothiocyanate, ITC)家族成员之一。越来越多流行病学和病理学研究证实PEITC可以诱导肿瘤细胞周期阻滞和凋亡。PEITC通过调节多种分子机制实现其抗肿瘤作用。本文对这些相关文献进行分析整理,对PEITC药物多靶向抗肿瘤作用机制和潜在的分子靶点进行简要综述。

关键词: 肿瘤治疗, β-异硫氰酸苯乙酯, 分子机制

Abstract: Cancer has very high mortality and increasing prevalence rates. And cancer therapy has become an important research topic in the scientific community and the medical profession. Phenethyl isothiocyanate (PEITC) is one of the most widely investigated isothiocyanates from the crucifers. Increasing evidences from epidemiological and pathological studies suggest that PEITC can induce cancer cell cycle arrest and apoptosis. It exerts its chemopreventive effect through regulation of diverse molecular mechanisms. Here, we summarize recent data regarding the multi-targeted anti-cancer activity mechanisms and potential molecular targets of PEITC.

Key words: cancer therapies, β-phenylethyl isothiocyanate, molecular mechanisms

中图分类号:

R965

张雪, 吴兰香, 张陶蓝, 温纯洁, 付利娟, 周宏灏. β-异硫氰酸苯乙酯多靶向抗肿瘤作用机制研究进展[J]. 中国临床药理学与治疗学, 2015, 20(2): 217-222.

ZHANG Xue, WU Lan-xiang, ZHANG Tao-lan, WEN Chun-jie, FU Li-juan, ZHOU Hong-hao. Advances in multi-targeted anti-tumor mechanisms of β-phenethyl isothiocyanate[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(2): 217-222.

参考文献

[1] Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer[J].Cell,2006,124(4):823-835.
[2] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer[J].Cell,2010,140(6):883-899.
[3] Pao W, Wang TY, Riely GJ,et al.KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib[J]. PLoS Med, 2005,2(1):e17.
[4] Couzin J.Cancer drugs. Smart weapons prove tough to design[J].Science,2002,298(5593):522-525.
[5] Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer[J].J Clin Oncol,2010,28(7):1254-1261.
[6] Haber DA, Settleman J. Overcoming acquired resistance to Iressa/Tarceva with inhibitors of a different class[J].Cell Cycle,2005,4(8):1057-1059.
[7] Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance[J].Cancer Lett,2006,232(2):123-138.
[8] Kopetz S. "Right drug for the right patient".Am Soc Clin Oncol Educ Book[M].2013,2013:115-120.
[9] Hecht SS. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism[J].J Nutr,1999,129(3):768S-774S.
[10]Hecht SS. Approaches to chemoprevention of lung cancer based on carcinogens in tobacco smoke[J].Environ Health Perspect,1997,105 Suppl 4:955-963.
[11]Ji Y, Morris ME. Determination of phenethyl isothiocyanate in human plasma and urine by ammonia derivatization and liquid chromatography-tandem mass spectrometry[J].Anal Biochem,2003,323(1):39-47.
[12]Liebes L, Conaway CC, Hochster H, et al. High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: application to studies with 2-phenethyl isothiocyanate[J].Anal Biochem,2001,291(1):279-289.
[13]Ji Y, Kuo Y, Morris ME. Pharmacokinetics of dietary phenethyl isothiocyanate in rats[J].Pharm Res,2005,22(10):1658-1666.
[14]Tusskorn O, Prawan A, Senggunprai L,et al. Phenethyl isothiocyanate induces apoptosis of cholangiocarcinoma cells through interruption of glutathione and mitochondrial pathway[J]. Naunyn Schmiedebergs Arch Pharmacol,2013, 386(11):1009-1016.
[15]Alwi SSS, Cavell BE, Donlevy A, et al. Differential induction of apoptosis in human breast cancer cell lines by phenethyl isothiocyanate, a glutathione depleting agent[J]. Cell Stress Chaperones,2012,17(5): 529-538.
[16]Hahm ER, Singh SV. Bim contributes to phenethyl isothiocyanate-induced apoptosis in breast cancer cells[J]. Mol Carcinog,2012,51(6): 465-474.
[17]Liu BN, Yan HQ, Wu X,et al. Apoptosis Induced by Benzyl Isothiocyanate in Gefitinib-Resistant Lung Cancer Cells is Associated withAkt/MAPK Pathways and Generation of Reactive Oxygen Species[J].Cell Biochem Biophys,2013,66(1):81-92.
[18]Bommareddy A, Hahm ER, Xiao D,et al. Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells[J].Cancer Res,2009,69(8):3704-3712.
[19]Loganathan S, Kandala PK, Gupta P et al. Inhibition of EGFR-AKT Axis Results in the Suppression of Ovarian Tumors In Vitro and in Preclinical Mouse Model[J]. PloS one, 2012,7(8):e43577.
[20]Zhang Y. The molecular basis that unifies the metabolism, cellular uptake and chemopreventive activities of dietary isothiocyanates[J]. Carcinogenesis,2012, 33(1):2-9.
[21]Xiao Z, Mi L, Chung FL,et al. Proteomic analysis of covalent modifications of tubulins by isothiocyanates[J].J Nutr,2012,142(7):1377S-1381S.
[22]Chen PY, Lin KC, Lin JP,et al. Phenethyl Isothiocyanate (PEITC) Inhibits the Growth of Human Oral Squamous Carcinoma HSC-3 Cells through G(0)/G(1) Phase Arrest and Mitochondria-Mediated Apoptotic Cell Death[J].Evid Based Complement Alternat Med,2012,2012:718320.
[23]Izzotti A, Larghero P, Cartiglia C,et al. Modulation of microRNA expression by budesonide, phenethyl isothiocyanate and cigarette smoke in mouse liver and lung[J].Carcinogenesis,2010,31(5):894-901.
[24]Slaby O, Sachlova M, Brezkova V,et al. Identification of MicroRNAs Regulated by Isothiocyanates and Association of Polymorphisms Inside Their Target Sites with Risk of Sporadic Colorectal Cancer[J]. Nutr Cancer,2013,65(2):247-254.
[25]Rudolph TK, Freeman BA. Transduction of redox signaling by electrophile-protein reactions[J].Sci Signal,2009,29,2(90):re7.
[26]Xu K, Thornalley PJ. Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro[J].Biochem Pharmacol,2001,61(2):165-77.
[27]Hu Y, Lu W, Chen G,et al. Overcoming resistance to histone deacetylase inhibitors in human leukemia with the redox modulating compound beta-phenylethyl isothiocyanate[J].Blood,2010,116(15):2732-2741.
[28]Lisa F Di, Kaludercic N, Carpi A,et al. Mitochondrial pathways for ROS formation and myocardial injury: the relevance of p66Shc and monoamine oxidase[J]. Basic Res Cardiol, 2009,104(2):131-139.
[29]Oshikawa J, Kim SJ, Furuta E,et al. Novel role of p66Shc in ROS-dependent VEGF signaling and angiogenesis in endothelial celsl[J].American Journal of Physiological,2012,302(3):H724-H732.
[30]Xiao D, Singh SV. p66Shc is indispensable for phenethyl isothiocyanate-induced apoptosis in human prostate cancer cells[J].Cancer Res,2010,70(8):3150-3158.
[31]Nemec KN, Khaled AR. Therapeutic modulation of apoptosis: targeting the BCL-2 family at the interface of the mitochondrial membrane[J].Yonsei Med J,2008,49(5):689-697.
[32]Douarre C, Gomez D, Morjani H,et al. Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence[J].Nucleic Acids Res,2005,33(7):2192-2203.
[33]Gazitt Y, Rothenberg ML, Hilsenbeck SG, et al. BcL-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells[J]. Int J Oncol, 1997,13(4):839-848.
[34]Thomson SJ, Brown KK, Pullar JM,et al. Phenethyl isothiocyanate triggers apoptosis in Jurkat cells made resistant by the overexpression of Bcl-2[J].Cancer Res,2006,66(13):6772-6777.
[35]Xiao D, Singh SV. Phenethyl isothiocyanate sensitizes androgen-independent human prostate cancer cells to docetaxel-induced apoptosis in vitro and in vivo[J].Pharm Res,2010,27(4):722-731.
[36]Satyan KS, Swamy N, Dizon DS,et al. Phenethyl isothiocyanate (PEITC) inhibits growth of ovarian cancer cells by inducing apoptosis: role of caspase and MAPK activation[J].Gynecol Oncol,2006,103(1):261-270.
[37]Wang H, Tan W, Hao B,et al.Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK[J].Cancer Res,2003,63(22):8057-8061.
[38]Tan W, Chen GF, Xing DY,et al.Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population[J].Int J Cancer,2001,95:96-101.
[39]DeVore NM, Smith BD, Wang JL,et al.Key residues controlling binding of diverse ligands to human cytochrome P450 2A enzymes[J].Drug Metab Dispos,2009,37:1319-1327.
[40]Pawlik A, Szczepanski MA, Klimaszewska A,et al.Phenethyl isothiocyanate-induced cytoskeletal changes and cell death in lung cancer cells[J].Food Chem Toxicol,2012,50(10):3577-94.
[41]Kischkel FC, Lawrence DA, Chuntharapai A,et al.Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5[J].Immunity,2000,12(6):611-620.
[42]Huong LD, Shim JH, Choi KH,et al.Effect of beta-phenylethyl isothiocyanate from cruciferous vegetables on growth inhibition and apoptosis of cervical cancer cells through the induction of death receptors 4 and 5[J].J Agric Food Chem,2011,59(15):8124-8131.
[43]Gerhauser C. Cancer chemoprevention and nutriepigenetics: state of the art and future challenges[J].Top Curr Chem,2013,329:73-132.
[44]Huang J, Plass C, Gerhauser C. Cancer chemoprevention by targeting the epigenome[J].Curr Drug Targets,2011,12(13):1925-1956.
[45]温纯洁,傅利娟,吴兰得,等. MiRNAs对细胞色素P450s药物代谢酶系调控作用的研究进展[J]. 中国临床药理学与治疗学,2011,16(11):1304-1309.
[46]Xiao J,Gong AY, Eischeid AN. miR-141 modulates androgen receptor transcriptional activity in human prostate cancer cells through targeting the small heterodimer partner protein[J].Prostate,2012,72(14):1514-1522.
[47]Wang H, Tan W, Hao B,et al. Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK[J].Cancer Res,2003,63(22):8057-8061.
[48]Alberto Izzotti. Chemoprevention of cigarette smoke-induced alterations of MicroRNA expression in rat lungs[J].Cancer Prev Res,2010,3(1):62-72.