Apo-10'-lycopenoic acid inhihits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo
Apo-10'-lycopenoic acid inhihits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo
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DOI：
10.1093/carcin/bgm076
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发表时间：
2007-07-01
期刊：
影响因子：
4.7
通讯作者：
Wang, Xiang-Dong
中科院分区：
文献类型：
--
作者：
Lian, Fuzhi;Smith, Donald E.;Wang, Xiang-Dong
番茄红素的高摄入量与包括肺癌在内的各种癌症的低风险有关。我们最近表明番茄红素可以转化为脱辅基-10 '-类番茄红素[Hu et al.（2006）. J. Biol. Chem.，281，19327-19338]在体外和体内的哺乳动物组织中，引发了apo-10 '-番茄红素是否具有抗肺癌发生的生物活性的问题。在本研究中，我们报告了apo-10 '-lyceroic acid抑制NHBE正常人支气管上皮细胞、BEAS-2B永生化正常支气管上皮细胞和A549非小细胞肺癌细胞的生长。脱辅基-10 '-甘草酸的这种抑制作用与细胞周期蛋白E的降低、细胞周期从G1期到S期的进展的抑制以及细胞周期调节因子p21和p27蛋白水平的增加有关。此外，apo-10 '-番茄红素酸反式激活视黄酸受体0（RAR β）启动子并诱导RAR β的表达。我们在A/J小鼠模型中进一步检查了脱辅基-10 '-甘草酸处理对4-（N-甲基-N-亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的肺肿瘤发生的作用。我们发现，肺肿瘤多样性从单独注射NNK组中每只小鼠平均16个肿瘤剂量依赖性地降低至注射NNK并分别补充10、40和120 mg/kg饮食的脱辅基-10 ′-赖氨酸的组中每只小鼠平均10、7和5个肿瘤。这些观察结果表明，脱辅基-10 '-番茄红素酸是番茄红素的生物活性代谢产物，并表明脱辅基-10'-番茄红素酸是一种潜在的肺肿瘤发生的化学预防剂。
High intake of lycopene has been associated with a lower risk of a variety of cancers including lung cancer. We recently showed that lycopene can be converted to apo-10'-lycopenoids [Hu et al. (2006). J. Biol. Chem., 281, 19327-19338] in mammalian tissues both in vitro and in vivo, raising the question of whether apo-10'-lycopenoids have biological activities against lung carcinogenesis. In the present study, we report that apo-10'-lycopenoic acid inhibited the growth of NHBE normal human bronchial epithelial cells, BEAS-2B-immortalized normal bronchial epithelial cells and A549 non-small cell lung cancer cells. This inhibitory effect of apo-10'-lycopenoic acid was associated with decreased cyclin E, inhibition of cell cycle progression from G, to S phase and increased cell cycle regulators p21 and p27 protein levels. In addition, apo-10'-lycopenoic acid transactivated the retinoic acid receptor 0 (RAR beta) promoter and induced the expression of RAR beta. We further examined the effect of apo-10'-lycopenoic acid treatment on 4-(N-methyl-N-nitrosamino)-1-(3-pyridal)-1-butanone (NNK)-induced lung tumorigenesis in the A/J mouse model. We found that the lung tumor multiplicity was decreased dose dependently from an average of 16 tumors per mouse in the NNK injection alone group, to an average of 10, 7 and 5 tumors per mouse in groups injected with NNK and supplemented with 10, 40 and 120 mg/kg diet of apo-10'-lycopenoic acid, respectively. These observations demonstrate that apo-10'-lycopenoic acid is a biological active metabolite of lycopene and suggest that apo-10'-lycopenoic acid is a potential chemopreventive agent against lung tumorigenesis.