8-Acetonyldihydronitidine (8-AHN) is a potent antitumor compound extracted from Toddalia asiatica. However, the precise molecular antitumor mechanisms of 8-AHN have not been well elucidated. Here, we showed that 8-AHN significantly inhibited the proliferation of human colorectal cell lines via induction of G2/M cell cycle arrest and apoptosis. We found that the p53 played a central role in 8-AHN-induced cell proliferation inhibition. Mechanistically, 8-AHN induced p53 expression and enhanced transcriptional activity, subsequently elevating the expression of p53 target genes, including p21, FAS, and BAX, and then increased the level of activated caspase-3 and decreased the level of cyclin B and cyclin A. Moreover, pifithrin-α, the p53 inhibitor, markedly reversed the above responses induced by 8-AHN, and small interfering RNA-mediated knockdown of TP53 also significantly decreased 8-AHN-induced cell apoptosis. The experiments in vivo showed that 8-AHN significantly suppressed the growth of HCT116 xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. In summary, 8-AHN displays an antitumor effect through cell cycle arrest and apoptosis in colorectal cells via activating p53, which suggests that 8-AHN, exerted a therapeutic potential against colorectal cancer cells, and may be regarded as an effective lead compound.

中文翻译：

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8-乙酰基二氢nitidine通过激活p53抑制人结肠直肠癌细胞的增殖。

8-乙酰基二氢nitidine（8-AHN）是一种有效的抗肿瘤化合物，其提取自Toddalia asiatica。但是，尚未很好地阐明8-AHN的确切分子抗肿瘤机制。在这里，我们表明8-AHN通过诱导G2 / M细胞周期停滞和凋亡显着抑制人结肠直肠细胞系的增殖。我们发现，p53在8-AHN诱导的细胞增殖抑制中起着核心作用。从机制上讲，8-AHN诱导p53表达并增强转录活性，随后升高p53靶基因（包括p21，FAS和BAX）的表达，然后增加激活的caspase-3的水平并降低cyclin B和cyclin A的水平此外，p53抑制剂pifithrin-α明显逆转了8-AHN诱导的上述反应，TP53的小干扰RNA介导的敲低也显着降低了8-AHN诱导的细胞凋亡。体内实验表明，8-AHN显着抑制了HCT116异种移植肿瘤的生长，与肿瘤组织中的增殖抑制和凋亡诱导有关，而没有引起任何明显的主要器官相关毒性。总之，8-AHN通过激活p53在大肠细胞中通过细胞周期停滞和凋亡显示出抗肿瘤作用，这表明8-AHN对大肠癌细胞具有治疗潜力，可以被视为有效的先导化合物。与肿瘤组织中的增殖抑制和凋亡诱导相关，而没有引起任何明显的主要器官相关毒性。总之，8-AHN通过激活p53在大肠细胞中通过细胞周期停滞和凋亡显示出抗肿瘤作用，这表明8-AHN对大肠癌细胞具有治疗潜力，可以被视为有效的先导化合物。与肿瘤组织中的增殖抑制和凋亡诱导有关，而没有引起任何明显的主要器官相关毒性。总之，8-AHN通过激活p53在大肠细胞中通过细胞周期停滞和凋亡显示出抗肿瘤作用，这表明8-AHN对大肠癌细胞具有治疗潜力，可以被视为有效的先导化合物。