tcsc6024 Xanthohumol

Xanthohumol is one of the principal flavonoids isolated from hops, the inhibitor of diacylglycerol acetyltransferase (DGAT), COX-1 and COX-2, and shows anti-cancer and anti-angiogenic activities.

In Vitro: Xanthohumol significantly attenuates ADP-induced blood platelet aggregation, and significantly reduces the expression of fibrinogen receptor (activated form of GPIIbIIIa) on platelets' surface^[1]. Xanthohumol (5-50 nM) reduces the frequency of spontaneously occurring Ca²⁺ sparks and Ca²⁺ waves in control myocytes and in cells subjected to Ca²⁺ overload caused by: (1) exposure to low K⁺ solutions, (2) periods of high frequency electrical stimulation, (3) exposures to isoproterenol or (4) caffeine. Xanthohumol (50-100 nM) reduces the rate of relaxation of electrically- or caffeine-triggered Ca²⁺ transients, without suppressing I_Ca, but this effect is small and reversed by isoproterenol at physiological temperatures. Xanthohumol also suppresses the Ca²⁺ content of the SR, and its rate of recirculation^[2]. Treatment of endothelial cells with Xanthohumol leads to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirm that AMPK mediates Xanthohumol anti-angiogenic activity. AMPK activation by Xanthohumol is mediated by CAMMKβ, but not LKB1. Analysis of the downstream mechanisms shows that Xanthohumol-induced AMPK activation reduces nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway is inactivated by Xanthohumol as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously^[3]. Xanthohumol significantly reduces cell viability and induces apoptosis via pro-caspase-3/8 cleavage and poly(ADP ribose) polymerase (PARP) degradation. Pro-caspase-9 cleavage, Bcl2 family expression changes, mitochondrial dysfunction, and intracellular ROS generation also participate in Xanthohumol-induced glioma cell death. Xanthohumol's inhibition of the IGFBP2/AKT/Bcl2 pathway via miR-204-3p targeting plays a critical role in mediating glioma cell death^[4].