Tified in colon, brain, and lung cancers (166). PI3K also includes a function within the

Tified in colon, brain, and lung cancers (166). PI3K also includes a function within the metastatic phenotype (167). A handful of nutraceuticals possess the demonstrated capability to inhibit PI3K. Ursolic acid therapy moderately decreased PI3K levels in two endometrial cancer cell lines, SNG-II and the poorly differentiated HEC108 cell line, and thus induced apoptosis (168). Recently, Tang and colleagues (169) showed that the proapoptotic effects of ursolic acid had been mediated by activation of caspase-3 and downregulation of survivin and have 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 recommended that diosgenin might be an effective inhibitor of hyper-pigmentation. Curcumin-mediated apoptotic effects had been observed in T-cell acute lymphoblastic leukemia malignant cells: curcumin suppressed constitutively activated targets of PI3K-kinase (AKT, FOXO, and GSK3), leading towards the inhibition of proliferation and induction of caspasedependent apoptosis (171). A recent study carried out by Chen et al. (172) showed that the amount of PI3K in melanoma tumor tissue was decrease within a curcumin-treated group (once each day at a dose of 100 mg/kg for 18 days) than the untreated handle group. AMPK–The AMPK can be a Ser/Thr protein kinase that was 1st identified by its activation by AMP and its ability 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., exercising, hypoxia, glucose PDGF-R-beta Proteins site 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 interest has been offered to linkage involving AMPK and cancer. AMPK, by regulating several downstream targets, like mTORC1, p53, FOXO, and fatty acid synthase, and linked metabolic processes, controls intracellular energy levels so as to preserve the cell development rate at an proper level. Likewise, AMPK activation beneath metabolic pressure or by pharmacological activators can regulate various processes, which includes 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 perhaps 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 in a p38-dependent MCP-1/CCL2 Proteins Storage & Stability 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 impacts the proliferation rate (180). Another study, conducted by Lee et al. (181), showed that curcumin exerted antitumorigenic effects by way of modulation on the AMPKCOX-2 cascade. Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 micromol/L and above. These apoptotic effects were correlated together with the decrease in phospho-Akt and COX-2, also as.