8-Acetonyldihydronitidine inhibits the proliferation of human colorectal cancer cells via activation of p53

Abstract

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.