Synthetic Caged Garcinia Xanthone Cluvenone Induces l Stress and Apoptosis and Has Immune

ownload eral caged Garcinia xanthone natural products have potent bioactivity and a documented value in onal Eastern medicine. Previous synthesis and structure activity relationship studies of these natural cts resulted in the identification of the pharmacophore represented by the structure of cluvenone. In the t study, we examined the anticancer activity of cluvenone and conducted gene expression profiling and ay analyses. Cluvenone was found to induce apoptosis in T-cell acute lymphoblastic leukemia C50 = 0.25 μmol/L) and had potent growth-inhibitory activity against the NCI60 cell panel, including that are multidrug-resistant, with a GI50 range of 0.1 to 2.7 μmol/L. Importantly, cluvenone was ximately 5-fold more potent against a primary B-cell acute lymphoblastic leukemia compared with eral blood mononuclear cells from normal donors, suggesting that it has significant tumor selectivity. arison of cluvenone's growth-inhibitory profile to those in the National Cancer Institute database ed that compounds with a similar profile to cluvenone were mechanistically unlike known agents, ere associated with cell stress and survival signaling. Gene expression profiling studies determined that one induced the activation of mitogen-activated protein kinase and NrF2 stress response pathways. rmore, cluvenone was found to induce intracellular reactive oxygen species formation. Lastly, the lation in the expression of several genes associated with T cell and natural killer cell activation and n by cluvenone suggests a role as an immune-modulator. The current work highlights the potential functio of cluvenone as a chemotherapeutic agent and provides support for further investigation of these intriguing molecules with regard to mechanism and targets. Mol Cancer Ther; 9(11); 2869–78. ©2010 AACR.