GSK-1292263A

Background: Piperidines are biogenic amines studied mainly in toxicology because they were initially found as alkaloids from peppers and insect venoms. Piperidines are also produced in the human body, and their actions seem to be related to wakefulness/sleep and other cognitive phenomena. Piperidines have been minimally characterized for therapeutic applications. In this context, 1-Boc-piperidine-4-carboxaldehyde (1-Boc-piperidine) is a piperidine-derivative molecule with no mechanism of action reported, although its uses include the synthesis of GPR119 selective agonists that have been patented as anti-obesity drugs. Objectives: The aim of this work was to study the effects of 1-Boc-piperidine on binge-eating behaviour and anxiety in Wistar rats. Methods: In experimental protocol 1, binge-eating behaviour was induced in animals that received pre-treatment (i.p.) with (i) vehicle (methanol 10%; 1 mL/kg), (ii) 1-Boc-piperidine (1 µmol kg⁻¹), or (iii) 1-Boc-piperidine (10 µmol kg⁻¹). In experimental protocol 2, mildly stressed animals were evaluated in the elevated plus maze under the acute effects of the pre-treatments applied in experimental protocol 1. Results and Conclusions: 1-Boc-piperidine decreased, in a dose-dependent manner, the intake of calories from a succulent hyper-caloric food in a binge-eating protocol in female rats, whereas the acute exposition to this piperidine exerted an anxiolytic effect in the male rat. In both effects, the mechanism of action remains to be characterized.

Ligand-dependent activation of the G-protein coupled receptor 119 (GPR119) lowers blood glucose via glucose-dependent insulin secretion and intestinal glucagon-like peptide-1 production. However, the function of GPR119 in cancer cells has not been studied.

GPR119 expression was assessed by real-time qPCR and immunohistochemistry in human breast cancer cell lines and breast cancer tissues. Cell proliferation and cell cycle analyses were performed by Incucyte® live cell analysis system and flow cutometry, respectively. Autophagy activity was estimeated by western blottings and LC3-GFP transfection.

mRNA or protein expression of GPR119 was detected in 9 cancer cell lines and 19 tissue samples. Cotreatment with GPR119 agonist (MBX-2982 or GSK1292263) significantly potentiated gefitinib-induced cell growth inhibition in gefitinib-insensitive MCF-7 and MDA-MB-231 breast cancer cells. We observed that caspase-3/7 activity was enhanced with the downregulation of Bcl-2 in MCF-7 cells exposed to MBX-2982. Gefitinib-induced autophagy is related with cancer cell survival and chemoresistance. GPR119 agonists inhibit gefitinib-induced autophagosome formation in MCF-7 and MDA-MB-231 cells. MBX-2982 also caused a metabolic shift to enhanced glycolysis accompanied by reduced mitochondrial oxidative phosphorylation. MBX-2982 increased intracellular (~ 2.5 mM) and extracellular lactate (~ 20 mM) content. Gefitinib-mediated autophagy was suppressed by 20 mM lactate in MCF-7 cells.

GPR119 agonists reduced mitochondrial OXPHOS and stimulated glycolysis in breast cancer cells, with consequent overproduction of lactate that inhibited autophagosome formation. Because autophagy is crucial for the survival of cancer cells exposed to TKIs, GPR119 agonists potentiated the anticancer effects of TKIs.