SB365, Pulsatilla saponin D, targets c-Met and exerts antiangiogenic and antitumor activities.

ABSTRACT

SB365, Pulsatilla saponin D isolated from the root of Pulsatilla koreana, has exhibited potential beneficial effects as a chemopreventive agent for critical health conditions including cancer. However, the molecular mechanisms underlying the activity of SB365 remain unknown. Here, we examined anticancer efficacy of SB365 against gastric cancer and its mechanism of action. SB365 effectively inhibited the growth of gastric cancer cells. Its apoptotic effect was accompanied by increased evidence of cleaved caspase-3 and poly(ADP ribose) polymerase. To elucidate the anticancer mechanism of SB365, we used an array of 42 different receptor tyrosine kinases (RTKs). Of the 42 different phospho-RTKs, SB365 strongly inhibited expression of activated c-mesenchymal-epithelial transition factor (c-Met) in gastric cancer cells. Also, the activation of the c-Met signal cascade components, including Akt and mammalian target of rapamycin, was inhibited by SB365 in a dose-dependent manner. In angiogenesis studies, SB365 inhibited tube formation in hepatocyte growth factor (HGF)-induced human umbilical vein endothelial cells and suppressed microvessel sprouting from the rat aortic ring, ex vivo, and blood vessel formation in the Matrigel plug assay in mice. In xenograft animal models, SB365 significantly delayed tumor growth in a dose-dependent manner. In tumor tissue, SB365 suppressed c-Met signaling, proliferation and angiogenesis and induced apoptosis. These findings suggest that SB365 docks at an allosteric site on c-Met and thereby targets c-Met signaling pathway, cell growth/angiogenesis inhibition and apoptosis induction. Therefore, SB365 may be a novel drug candidate for the treatment of gastric cancer.