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首页> 外文学位 >The induction of phase II detoxifying enzymes and prostate cancer prevention by chemopreventive isothiocyanates.
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The induction of phase II detoxifying enzymes and prostate cancer prevention by chemopreventive isothiocyanates.

机译：化学预防异硫氰酸盐诱导II期排毒酶和预防前列腺癌。

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摘要

Epidemiological studies have revealed an inverse correlation between the intake of cruciferous vegetables and the risk of cancer. Many experimental animal studies suggest that the anti-cancerous effect of cruciferous vegetables can be ascribed to a high abundance of glucosinolates, chemical precursors of chemopreventive isothiocyanates. Although the molecular pathways mediating the anti-tumoral effects of isothicyanates, such as phenethyl isothiocyanate (PEITC) and sulforaphane, have not been fully elucidated, it is known that they strongly induce phase II detoxifying enzymes (HO-1, NQO1 and UGT1A1) by NF-E2-related factor 2 (Nrf2)-mediated activation of antioxidant response element (ARE), which is positively regulated by ERK1/2 and JNK1/2, but negatively regulated by p38 MAPK. Treatment of PEITC or sulforaphane activated ERK1/2 and JNK1/2, but inhibited anisomycin-induced activation of p38 MAPK isoforms. In pursuit of synthetic isothiocyanates that exhibit strong ARE-dependent gene activation, 3-morpholinorpropyl isothiocyanate (3-MP-ITC) was identified as a novel isothiocyanate, whose ARE activation was superior to PEITC and sulforaphane. While continued intraperitoneal injection of curcumin or PEITC, beginning a day before tumor implantation significantly retarded the growth of PC-3 xenografts in nude mice, curcumin and PEITC in combination, but not PEITC or curcumin alone, significantly suppressed the growth of established PC-3 xenografts. Also, oral administration of broccoli sprouts for 16 weeks significantly inhibited the prostate tumor growth in TRAMP mice not only by the induction of Nrf2 and apoptosis, but also by the suppression of Akt/mTOR pathway. Finally, exposure of a phenolic antioxidant, butylated hydroxyanisole (BHA) or its metabolite, tert-butyl hydroquinone (tBHQ) to primary-cultured human and rat hepatocytes strongly activated ERK1/2 and JNK1/2 and induced Nrf2, HO-1 and NQO1 proteins. This dissertation clearly demonstrates that isothiocyanates induce Nrf2/ARE-dependent gene activation and the expression of phase II detoxifying enzymes by activating ERK1/2 and JNK1/2 and inhibiting p38 MAPK pathways. Also, it provides the clear evidence of prostate carcinogenesis suppression by isothiocyanates and the underlying biochemical mechanisms in vivo. Together, this dissertation will contribute to better understanding how chemopreventive isothiocyanates regulate the cellular protective mechanisms and prevent against prostate carcinogenesis.
机译：流行病学研究表明，十字花科蔬菜的摄入量与患癌症的风险呈负相关。许多实验动物研究表明，十字花科蔬菜的抗癌作用可归因于高含量的芥子油苷，这是化学预防性异硫氰酸盐的化学前体。尽管尚未充分阐明介导异硫氰酸酯（如异硫氰酸苯乙酯（PEITC）和萝卜硫烷）的抗肿瘤作用的分子途径，但已知它们能通过下列方式强烈诱导II期解毒酶（HO-1，NQO1和UGT1A1） NF-E2相关因子2（Nrf2）介导的抗氧化反应元件（ARE）的激活受到ERK1 / 2和JNK1 / 2的正调控，但受p38 MAPK的负调控。 PEITC或萝卜硫素的治疗激活了ERK1 / 2和JNK1 / 2，但抑制了茴香霉素诱导的p38 MAPK亚型的激活。为了追求表现出强烈的ARE依赖性基因激活的合成异硫氰酸酯，3-吗啉基丙基异硫氰酸酯（3-MP-ITC）被确定为一种新型异硫氰酸酯，其ARE激活优于PEITC和萝卜硫烷。在继续腹膜内注射姜黄素或PEITC的同时，从肿瘤植入前一天开始，裸鼠明显延迟了PC-3异种移植物的生长，姜黄素和PEITC联合使用，但单独使用PEITC或姜黄素则没有明显抑制已建立的PC-3的生长。异种移植。此外，口服西兰花芽菜持续16周不仅通过诱导Nrf2和细胞凋亡，而且通过抑制Akt / mTOR途径来显着抑制TRAMP小鼠的前列腺肿瘤生长。最后，将酚类抗氧化剂丁基化羟基茴香醚（BHA）或其代谢产物叔丁基对苯二酚（tBHQ）暴露于原代培养的人和大鼠肝细胞中会强烈激活ERK1 / 2和JNK1 / 2，并诱导Nrf2，HO-1和NQO1蛋白质。这篇论文清楚地表明，异硫氰酸酯通过激活ERK1 / 2和JNK1 / 2并抑制p38 MAPK途径来诱导Nrf2 / ARE依赖性基因激活和II期解毒酶的表达。同样，它提供了异硫氰酸盐抑制前列腺癌发生的明确证据以及体内潜在的生化机制。总之，本论文将有助于更好地理解化学预防异硫氰酸酯如何调节细胞保护机制并预防前列腺癌的发生。

著录项

  • 作者

    Keum, Young-Sam.;

  • 作者单位

    Rutgers The State University of New Jersey - New Brunswick.;

  • 授予单位 Rutgers The State University of New Jersey - New Brunswick.;
  • 学科 Health Sciences Pharmacology.; Chemistry Biochemistry.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 203 p.
  • 总页数 203
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;生物化学;肿瘤学;
  • 关键词

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