Role of AMP-Activated Protein Kinase Activators in Antiproliferative Multi-Drug Pituitary Tumour Therapies: Effects of Combined Treatments with Compounds Affecting the mTOR-p70S6 Kinase Axis in Cultured Pituitary Tumour Cells

摘要: AMP-activated protein kinase (AMPK) is activated under conditions that deplete cellular ATP levels and elevate AMP levels. We have recently shown AMPK can represent a valid target for improving the medical treatment of growth hormone (GH)-secreting pituitary adenomas effects its activation or inhibition in tumour cells are worthy further characterisation. aimed to determine whether may role combined antiproliferative therapies based on multiple drugs targeting cell anabolic functions at different overcome risk escape phenomena. Accordingly, we tried rationale exists combining compounds activating with phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR/p70S6K signalling pathway. down-regulation by specific small-interfering RNAs confirmed had restraining GH3 cells. Hence, compared directly mTOR-p70S6K axis, namely mTOR inhibitor rapamycin p70S6K PF-4708671, activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) growth, rat AICAR was able reduce factor-induced activity, as decrease phospho-p70S6K However, it far less effective than PF-4708671. observed significant differences between inhibitory three GH1 Interestingly, PF-4708671 devoid any effect. least co-treatment more single treatments. induced apoptosis cells, whereas caused preferentially proliferation. Finally, differed their actions extracellular signal regulated 1/2 phosphorylation. In conclusion, results present study suggest increased efficacy therapies, including analogues activators GH-secreting tumours, result complementary only partially overlapping mechanisms action.