Purvalanol A Exerts Anti‐Hepatocellular Carcinoma Activity by Activating the p53 Pathway

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is characterized by a complex pathogenesis and high mortality rate. Currently, there is a lack of effective therapeutic agents for HCC. This study aimed to identify potential targeted therapeutic compounds for HCC and to validate their mechanisms of action through in vitro and in vivo experiments. Using the Connectivity Map database, we screened compounds capable of influencing the status of core genes and selected those predicted to be nontoxic for experimental validation. Our findings demonstrated that, within a certain concentration range (0-80 μM), Purvalanol A significantly inhibited the viability and proliferation of HCC cell lines Huh7 and Hepa1-6. Notably, the IC50 value for normal human liver cells (THLE-2) was much higher than that for HCC cells, indicating selective cytotoxicity. Purvalanol A also suppressed the migration and invasion abilities of HCC cells, induced G2/M cell cycle arrest, and promoted apoptosis. Additionally, Purvalanol A treatment downregulated the expression of the key gene CDK1 (cyclin-dependent kinases) and the antiapoptotic protein Bcl2 while upregulating the expression of p53, phosphorylated p53 (p-p53), and the p53 downstream proapoptotic protein Bax, moreover, the ratio of p-p53/p53 increased, indicating activation of the p53 pathway. In a mouse xenograft tumor model, Purvalanol A significantly inhibited subcutaneous tumor growth without causing noticeable toxicity to internal organs. In conclusion, the results of this study suggest that Purvalanol A exerts anti-HCC effects by activating the p53 pathway, making it a potential therapeutic compound for the treatment of hepatocellular carcinoma.