The Natural Alkaloid (-)-N-Hydroxyapiosporamide Suppresses Colorectal Tumor Progression as an NF-B Pathway Inhibitor by Targeting the TAK1-TRAF6 Complex

Colorectal cancer (CRC) is an exceptionally deadly disease,whereaseffective therapeutic drugs for CRC have declined over the past fewdecades. Natural products have become a reliable source of anticancerdrugs. Previously we isolated an alkaloid named (-)-N-hydroxyapiosporamide (NHAP), which exerts potent antitumoreffects, but its effect and mechanism in CRC remain unclear. Thisstudy aimed to reveal the antitumor target of NHAP and identify NHAPas a promising lead compound for CRC. Various biochemical methodsand animal models were used to investigate the antitumor effect andmolecular mechanism for NHAP. These results showed that NHAP exhibitedpotent cytotoxicity, induced both apoptosis and autophagic cell deathof CRC cells, and inhibited the NF-kappa B signaling pathway by blockingthe interaction of the TAK1-TRAF6 complex. NHAP also markedlyinhibited CRC tumor growth in vivo without obvioustoxicities and possessed good pharmacokinetic characteristics. Thesefindings identify, for the first time, that NHAP is an NF-kappa Binhibitor with potent antitumor activity in vitro and in vivo. This study clarifies the antitumortarget of NHAP against CRC, which will contribute to the future developmentof NHAP as a novel therapeutic lead compound for CRC.