Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling
Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling
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DOI：
10.1111/jpi.12142
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发表时间：
2014-08-01
影响因子：
10.3
通讯作者：
Samaja, Michele
中科院分区：
文献类型：
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作者：
Paroni, Rita;Terraneo, Laura;Samaja, Michele
众所周知，褪黑素在几种人类癌症中发挥抗肿瘤活性，但其潜在机制以及不同剂量褪黑素的功效尚未明确。在这里，我们验证了纳米摩尔范围内的褪黑激素是否能有效发挥体内抗肿瘤活性的假设，并研究了其与缺氧信号机制的相关性，这可能是褪黑激素拮抗肿瘤的主要分子机制。为了验证这一假设，将LNCaP人类前列腺癌细胞移植到7周大的Foxn1nu/nu雄性小鼠中，并给予褪黑激素（41天内注射18次，剂量为1 mg/kg）。盐水处理小鼠作为对照组。我们发现血浆和异种移植组织中的褪黑素水平分别比对照样品高4倍和60倍。褪黑素倾向于通过增加Nrf2的表达来恢复氧化还原失衡。作为对这些干扰的表型反应的一部分，褪黑激素处理的动物的异种移植物微血管密度较低，表明血管生成较低，并且异种移植物生长速度较慢（P < 0.0001）。与盐水处理的小鼠相比，这些变化伴随着Ki67的表达减少，HIF-1 α的表达升高以及褪黑激素中Akt磷酸化的增加。我们得出结论，褪黑素在体内减少癌症生长的有益作用在褪黑素血浆水平低至4 nM时是明显的，并且与血管生成减少有关。异种移植物组织中较高的HIF-1 α表达表明抗肿瘤作用不是由于假定的抗缺氧作用，而可能源于较低的血管生成潜力。
Melatonin is known to exert antitumour activity in several types of human cancers, but the underlying mechanisms as well as the efficacy of different doses of melatonin are not well defined. Here, we test the hypothesis whether melatonin in the nanomolar range is effective in exerting antitumour activity in vivo and examine the correlation with the hypoxia signalling mechanism, which may be a major molecular mechanism by which melatonin antagonizes cancer. To test this hypothesis, LNCaP human prostate cancer cells were xenografted into seven-wk-old Foxn1nu/nu male mice that were treated with melatonin (18 i. p. injections of 1 mg/kg in 41 days). Salinetreated mice served as control. We found that the melatonin levels in plasma and xenografted tissue were 4x and 60x higher, respectively, than in control samples. Melatonin tended to restore the redox imbalance by increasing expression of Nrf2. As part of the phenotypic response to these perturbations, xenograft microvessel density was less in melatonin-treated animals, indicative of lower angiogenesis, and the xenograft growth rate was slower (P < 0.0001). These changes were accompanied by a reduced expression of Ki67, elevated expression of HIF-1 alpha and increased phosphorylation of Akt in melatonin than saline-treated mice. We conclude that the beneficial effect of melatonin in reducing cancer growth in vivo was evident at melatonin plasma levels as low as 4 nM and was associated with decreased angiogenesis. Higher HIF-1 alpha expression in xenograft tissue indicates that the antitumour effect cannot be due to a postulated antihypoxic effect, but may stem from lower angiogenesis potential.