Moreno-SanJuan Sara, Puentes-Pardo Jose D, Casado Jorge, Escudero-Feliu Julia, Khaldy Huda, Arnedo Javier, Carazo Ángel, León Josefa
Cytometry and Microscopy Research Service, Biosanitary Research Institute of Granada (ibs.GRANADA), 18012 Granada, Spain.
Biosanitary Research Institute of Granada (ibs.GRANADA), 18012 Granada, Spain.
Antioxidants (Basel). 2023 Apr 13;12(4):926. doi: 10.3390/antiox12040926.
The potential use of agomelatine as an alternative treatment for colorectal cancer is evaluated in this work. The effect of agomelatine was studied in an in vitro model using two cell lines with different p53 statuses (HCT-116, wild-type p53, and HCT-116 p53 null) and an in vivo xenograft model. The inhibitory effects of agomelatine and melatonin were stronger in the cells harboring the wild-type p53, although in both cell lines, the effect of agomelatine was greater than that of the melatonin. In vivo, only agomelatine was able to reduce the volumes of tumors generated by the HCT-116-p53-null cells. Both treatments induced changes in the rhythmicity of the circadian-clock genes in vitro, albeit with some differences. Agomelatine and melatonin regulated the rhythmicity of Per1-3, Cry1, Sirt1, and Prx1 in the HCT-116 cells. In these cells, agomelatine also regulated Bmal1 and Nr1d2, while melatonin changed the rhythmicity of Clock. In the HCT-116-p53-null cells, agomelatine regulated Per1-3, Cry1, Clock, Nr1d2, Sirt1, and Prx1; however, melatonin only induced changes in Clock, Bmal1, and Sirt1. The differences found in the regulation of the clock genes may explain the greater oncostatic effect of agomelatine in CRC.
本研究评估了阿戈美拉汀作为结直肠癌替代治疗方法的潜在用途。在体外模型中，使用两种具有不同p53状态的细胞系（HCT-116，野生型p53，以及HCT-116 p53缺失型）和体内异种移植模型研究了阿戈美拉汀的作用。阿戈美拉汀和褪黑素对野生型p53细胞的抑制作用更强，尽管在两种细胞系中，阿戈美拉汀的作用均大于褪黑素。在体内，只有阿戈美拉汀能够减小HCT-116-p53缺失型细胞产生的肿瘤体积。两种治疗均在体外诱导了昼夜节律时钟基因节律性的变化，尽管存在一些差异。阿戈美拉汀和褪黑素调节了HCT-116细胞中Per1-3、Cry1、Sirt1和Prx1的节律性。在这些细胞中，阿戈美拉汀还调节了Bmal1和Nr1d2，而褪黑素改变了Clock的节律性。在HCT-116-p53缺失型细胞中，阿戈美拉汀调节了Per1-3、Cry1、Clock、Nr1d2、Sirt1和Prx1；然而，褪黑素仅诱导了Clock、Bmal1和Sirt1的变化。在时钟基因调节方面发现的差异可能解释了阿戈美拉汀在结直肠癌中更大的抑癌作用。
