Tified in colon, brain, and lung cancers (166). PI3K also has a function inside the metastatic phenotype (167). A couple of nutraceuticals possess the demonstrated capability to inhibit PI3K. Ursolic acid treatment moderately decreased PI3K levels in two endometrial cancer cell lines, SNG-II and the poorly differentiated HEC108 cell line, and hence induced apoptosis (168). Recently, Tang and colleagues (169) showed that the proapoptotic effects of ursolic acid were mediated by activation of caspase-3 and downregulation of survivin and were very CD127/IL-7RA Proteins Storage & Stability correlated with inactivation of PI3K/Akt/survivin pathway in human HepG2 cells. Lee et al. (170) reported that diosgenin inhibits melanogenesis by activating the PI3K pathway and also recommended that diosgenin might be an efficient inhibitor of hyper-pigmentation. Curcumin-mediated apoptotic effects had been observed in T-cell acute lymphoblastic leukemia malignant cells: curcumin suppressed TIE-1 Proteins Accession constitutively activated targets of PI3K-kinase (AKT, FOXO, and GSK3), top for the inhibition of proliferation and induction of caspasedependent apoptosis (171). A recent study performed by Chen et al. (172) showed that the degree of PI3K in melanoma tumor tissue was reduced within a curcumin-treated group (once a day at a dose of one hundred mg/kg for 18 days) than the untreated handle group. AMPK–The AMPK is really a Ser/Thr protein kinase that was very first identified by its activation by AMP and its capability to phosphorylate and inactivate enzymes involved in lipid and cholesterol synthesis (173). In the cellular level, AMPK is activated by metabolic stressors that deplete ATP and enhance AMP (e.g., physical exercise, hypoxia, glucose deprivation) (174). AMPK activation enhances insulin sensitivity, inhibits hepatic glucose production, stimulates glucose uptake in muscle, inhibits fatty acid synthesis and esterification, and diminishes proinflammatory modifications (175). It has been shown that AMPK phosphorylates tuberous sclerosis complex-2 (a bona fide tumor suppressor) to inhibit mTOR signals (176). This observation reveals a direct connection of AMPK with cancer. Recently, fantastic interest has been given to linkage in between AMPK and cancer. AMPK, by regulating numerous downstream targets, for example mTORC1, p53, FOXO, and fatty acid synthase, and associated metabolic processes, controls intracellular energy levels as a way to preserve the cell growth rate at an proper level. Likewise, AMPK activation under metabolic strain or by pharmacological activators can regulate several processes, such as cell cycle checkpoint, cell polarity, senescence, autophagy, and apoptosis (177,178).NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptNutr Cancer. Author manuscript; accessible in PMC 2013 May possibly 06.Sung et al.PageAs has been the case for many other targets in the cancer cell signaling pathways, curcumin strongly activates AMPK, in this case within a p38-dependent manner in CaOV3 ovarian cancer cells, therefore inducing cell death (179). Stimulation of AMPK by curcumin downregulates PPAR in 3T3-L1 adipocytes and decreases COX-2 expression in MCF-7 cells, which in turn affects the proliferation rate (180). Another study, performed by Lee et al. (181), showed that curcumin exerted antitumorigenic effects by way of modulation of the AMPKCOX-2 cascade. Curcumin exhibited a potent apoptotic impact on HT-29 colon cancer cells at concentrations of 50 micromol/L and above. These apoptotic effects have been correlated with all the decrease in phospho-Akt and COX-2, also as.