Tified in colon, brain, and lung cancers (166). PI3K also has a part inside the metastatic phenotype (167). A number of nutraceuticals possess the demonstrated capability to inhibit PI3K. Ursolic acid remedy moderately decreased PI3K levels in 2 endometrial cancer cell lines, SNG-II and the poorly differentiated P2X7 Receptor Inhibitor drug HEC108 cell line, and therefore induced apoptosis (168). Lately, Tang and colleagues (169) showed that the proapoptotic effects of ursolic acid were mediated by activation of caspase-3 and downregulation of survivin and had been hugely 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 as well as suggested that diosgenin might be an effective inhibitor of hyper-pigmentation. Curcumin-mediated apoptotic effects have been observed in T-cell acute lymphoblastic leukemia malignant cells: MEK Inhibitor Storage & Stability curcumin suppressed constitutively activated targets of PI3K-kinase (AKT, FOXO, and GSK3), top to the inhibition of proliferation and induction of caspasedependent apoptosis (171). A recent study conducted by Chen et al. (172) showed that the level of PI3K in melanoma tumor tissue was reduced within a curcumin-treated group (when a day at a dose of 100 mg/kg for 18 days) than the untreated control group. AMPK–The AMPK is a Ser/Thr protein kinase that was 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 raise 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 alterations (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. Lately, terrific attention has been given to linkage involving AMPK and cancer. AMPK, by regulating numerous downstream targets, which include mTORC1, p53, FOXO, and fatty acid synthase, and connected metabolic processes, controls intracellular energy levels in order to retain the cell growth rate at an acceptable level. Likewise, AMPK activation under metabolic anxiety or by pharmacological activators can regulate various processes, including 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; out there in PMC 2013 May possibly 06.Sung et al.PageAs has been the case for many other targets within the cancer cell signaling pathways, curcumin strongly activates AMPK, within this case in a p38-dependent manner in CaOV3 ovarian cancer cells, hence 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 price (180). A further study, performed by Lee et al. (181), showed that curcumin exerted antitumorigenic effects through 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 were correlated with the lower in phospho-Akt and COX-2, as well as.