Silibinin prevents lung tumorigenesis in wild-type but not in iNOS-/- mice: potential of real-time micro-CT in lung cancer chemoprevention studies.
Silibinin prevents lung tumorigenesis in wild-type but not in iNOS-/- mice: potential of real-time micro-CT in lung cancer chemoprevention studies.
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DOI：
10.1158/1078-0432.ccr-10-2290
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发表时间：
2011-02-15
期刊：
影响因子：
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通讯作者：
Agarwal R
中科院分区：
文献类型：
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作者：
Ramasamy K;Dwyer-Nield LD;Serkova NJ;Hasebroock KM;Tyagi A;Raina K;Singh RP;Malkinson AM;Agarwal R
持续的一氧化氮（NO）生成与肺癌的发生和进展呈正相关。在此，我们从遗传学上证实了iNOS的这种作用，并评估了水飞蓟宾在致癌物处理的B6/129野生型（WT）和iNOS−/−小鼠中的化学预防功效。雄性B6/129-Nos 2 tm 1 Lau（iNOS-/-）和B6/129 PF 2 WT小鼠每周一次连续7周腹膜内注射1 mg/g体重的氨基甲酸乙酯，然后连续18周每周5天灌胃水飞蓟宾（742 mg/kg体重）。实时定量微CT数据显示，水飞蓟宾显著降低WT小鼠中的肿瘤诱导的肿瘤数量和大小，这与在研究结束时进行的离体测量一致。与WT小鼠相比，iNOS的基因切除使小鼠诱导的肿瘤多样性降低了87%（P<0.001）。水飞蓟宾在WT小鼠中使肿瘤多样性降低了71%（P<0.01），但在iNOS−/−小鼠中没有显示出任何显著的效果。野生型小鼠肿瘤组织中iNOS的表达明显高于水飞蓟宾组（P<0.01），eNOS和nNOS的表达与水飞蓟宾组相似。在这些肿瘤中，水飞蓟宾中度（P<0.01）抑制细胞增殖，但强烈（P<0.01）减少新形成的nestin阳性微血管的数量。水飞蓟宾可降低肿瘤组织中VEGF 2的表达，降低肿瘤组织中STAT 3和NF-κB的活化。水飞蓟宾在iNOS−/−小鼠中缺乏作用表明，水飞蓟宾通过抑制肺肿瘤中的iNOS表达发挥其大部分化学预防和血管预防作用。我们的研究结果支持iNOS作为控制肺癌的潜在靶点，并证明了实时非侵入性micro-CT成像模式对评估肺癌化学预防剂的疗效的价值。
Sustained nitric oxide (NO) generation positively correlates with lung cancer development and progression. Herein, we genetically confirmed this role of iNOS and evaluated the chemopreventive efficacy of silibinin in carcinogen-treated B6/129 wild-type (WT) and iNOS−/− mice. Male B6/129-Nos2tm1Lau (iNOS −/−) and B6/129PF2 WT mice were injected i.p. with 1mg/g body weight urethane once weekly for 7 consecutive weeks, followed by silibinin gavage (742mg/kg body weight) for 5 days/week for 18 weeks. Quantification of micro-CT data in real-time showed that silibinin significantly decreases urethane-induced tumor number and size in WT mice, consistent with measurements made ex vivo at study termination. Genetic ablation of iNOS decreased urethane-induced tumor multiplicity by 87% (P<0.001) compared to WT mice. Silibinin decreased tumor multiplicity by 71% (P<0.01) in WT mice, but did not show any such considerable effect in iNOS−/− mice. Tumors from WT mice expressed more iNOS (P<0.01) but almost similar eNOS and nNOS than those in silibinin-treated mice. In these tumors, silibinin moderately (P<0.01) inhibited cell proliferation but strongly (P<0.01) reduced the number of newly formed nestin-positive microvessels. Silibinin decreased VEGFR2 level, and STAT3 and NF-κB activation in tumors. The lack of effect of silibinin in iNOS−/− mice suggests that silibinin exerts most of its chemopreventive and angiopreventive effects through its inhibition of iNOS expression in lung tumors. Our results support iNOS as a potential target for controlling lung cancer, and demonstrate the value of real-time non-invasive micro-CT imaging modality for evaluating the efficacy of lung cancer chemopreventive agents.