Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest
Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest
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DOI：
10.1093/carcin/bgh136
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发表时间：
2004-08-01
期刊：
影响因子：
4.7
通讯作者：
Liu, DL
中科院分区：
文献类型：
--
作者：
Chiao, JW;Wu, HY;Liu, DL
流行病学调查表明，十字花科蔬菜的摄入量与前列腺癌的发病率呈负相关，尽管负责的饮食因素尚未确定。我们的研究表明，暴露于培养的人前列腺癌细胞的N-乙酰半胱氨酸（NAC）的苯乙基异硫氰酸酯（PEITC-NAC），PEITC的主要代谢产物，是丰富的豆瓣菜，抑制增殖和肿瘤发生的共轭物。已知PEITC-NAC在癌发生开始时介导细胞保护。已经在具有人前列腺癌PC-3细胞的异种移植肿瘤的免疫缺陷小鼠中评价了饮食中的PEITC-NAC对前列腺肿瘤细胞生长的相关性。每日补充PEITC-NAC（8 μ mol/g）的饮食组显示，在9周的治疗期间，100%的小鼠肿瘤大小显著减小。与不含PEITC-NAC的饮食的小鼠相比，尸检时的肿瘤重量减少了50%（P = 0.05）。在这些肿瘤中，有丝分裂和体内5-溴-2 '-脱氧尿苷标记的增殖细胞减少。PEITC-NAC饮食上调了细胞周期蛋白依赖性激酶p21（WAF-1/Cip-1）和p27（Kip 1）的抑制剂，并降低了细胞周期蛋白D和E的表达，表明它们是潜在的分子靶点。其结果是，磷酸化Rb显着减少，G（1）-到S-相变延迟。经处理的肿瘤也显示出凋亡的显着增加，如通过原位末端标记和聚ADP-核糖聚合酶切割所确定的。这项研究证明了饮食PEITC-NAC抑制前列腺癌细胞肿瘤发生的第一个体内证据。PEITC-NAC可以通过靶向细胞周期调节因子和凋亡诱导来防止癌变的开始并调节启动后阶段。
Epidemiological surveys indicate that intake of cruciferous vegetables is inversely related to prostate cancer incidence, although the responsible dietary factors have not been identified. Our studies demonstrated that exposure of human prostate cancer cells in culture to the N-acetylcysteine (NAC) conjugate of phenethyl isothiocyanate (PEITC-NAC), the major metabolite of PEITC that is abundant in watercress, inhibited proliferation and tumorigenesis. The PEITC-NAC is known to mediate cytoprotection at initiation of carcinogenesis. The relevance of PEITC-NAC in diets on the growth of prostate tumor cells has been evaluated in immunodeficient mice with xenografted tumors of human prostate cancer PC-3 cells. The daily PEITC-NAC (8 mumol/g) supplemented diet group showed a significant reduction in tumor size in 100% of the mice during the 9-week treatment period. Tumor weight at autopsy was reduced by 50% compared with mice on the diet without PEITC-NAC (P = 0.05). Mitosis and in vivo 5-bromo-2'-deoxyuridine labeled proliferating cells were reduced in these tumors. The PEITC-NAC diet up-regulated the inhibitors of cyclin-dependent kinases p21(WAF-1/Cip-1) and p27(Kip1), and reduced the expression of cyclins D and E, indicating they were potential molecular targets. As a result, phosphorylated Rb was significantly decreased and the G(1)- to S-phase transition retarded. The treated tumors also showed a significant increase in apoptosis as determined by in situ end-labeling, and by poly ADP-ribose polymerase cleavage. This study demonstrates the first in vivo evidence of dietary PEITC-NAC inhibiting tumorigenesis of prostate cancer cells. PEITC-NAC may prevent initiation of carcinogenesis and modulate the post-initiation phase by targeting cell cycle regulators and apoptosis induction.