The activation of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway is a known causal mechanism of oncogenesis and resistance to cancer treatments. The process of PI3K-Akt pathway activation is complex and includes receptor tyrosine kinase(RTK) activation, PIK3CA mutations, loss of phosphatase and tensin homolog (PTEN), Akt mutations, tuberous sclerosis complex (TSC) mutations, and Ras homologue enriched in brain (RHEB) gene amplifications. The blockage of mammalian target of rapamycin (mTOR), the key downstream pathway protein, has been successful in selected cancer types, with mTOR-targeting agents available for clinical use. Other novel drugs blocking this pathway such as PI3K inhibitors, Akt inhibitors and PDK-1 inhibitors are currently only available for investigational use, but have shown promise as cancer therapies in both preclinical and early phase clinical studies. The newer generations of these inhibitors are more specific and have improved potency and safety. The combinations of targeted treatments against this pathway, blocking multiple different steps, are under preliminary investigation. Further research is needed to identify the biomarkers that predict treatment response and resistance in order to optimize personalized medicine.
"The efficacy of mTORC1 inhibitors is limited by dysregulation of negative feedback loops and a lack of mTORC2 inhibition  . Promisingly, a preclinical study evaluating the efficacy of dual mTORC1/2 inhibition showed blockade of compensatory AKT Table 1 Selected clinical trials of synthetic small molecule inhibitors in metastatic melanoma. "
"Advanced studies led to the development of inhibitors of PI3K which selectively target only the catalytic sites (75). The new PI3Ka isoform-specific inhibitors gave an effective response in cell lines that present PIK3CA mutations (76,77). "
[Show abstract][Hide abstract] ABSTRACT: Cutaneous melanoma is an aggressive cancer with a poor prognosis for patients with advanced disease. The identification of several key molecular pathways implicated in the pathogenesis of melanoma has led to the development of novel therapies for this devastating disease. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways are constitutively activated through multiple mechanisms. Targeting various effectors of these pathways with pharmacologic inhibitors may inhibit melanoma cell growth and angiogenesis. Ongoing clinical trials provide hope to improve progression-free survival of patients with advanced melanoma. This review summarizes the most relevant studies focused on the specific action of these new molecular targeted agents. Mechanisms of resistance to therapy are also discussed.
International Journal of Oncology 06/2014; 45(2). DOI:10.3892/ijo.2014.2481 · 3.03 Impact Factor
"Glycogen synthase kinase-3β (GSK-3β) is one of the major downstream substrate of PI3K/Akt pathway, and has been demonstrated to modulate the activity of PPAR-α , . We then investigated the effects of ethanol and CMZ on several important factors involved in PI3K/Akt/GSK-3β pathway. "
[Show abstract][Hide abstract] ABSTRACT: Background
Cytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms.
Mice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods.
CYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3β pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ.
These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.
PLoS ONE 06/2014; 9(6):e98658. DOI:10.1371/journal.pone.0098658 · 3.23 Impact Factor
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