Combined treatment of MCF-7 cells with AICAR and methotrexate, arrests cell cycle and reverses Warburg metabolism through AMP-activated protein kinase (AMPK) and FOXO1

Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK) jointly with methotrexate (MTX), a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer

Glycogen phosphorylase inhibitor N-(3,5-dimethyl-benzoyl)-N'-(β-Dglucopyranosyl) urea improves glucose tolerance under normoglycemic and diabetic conditions and rearranges hepatic metabolism

Glycogen phosphorylase (GP) catalyzes the breakdown of glycogen and largely contributes to hepatic glucose production making GP inhibition an attractive target to modulate glucose levels in diabetes. Hereby we present the metabolic effects of a novel, potent, glucose-based GP inhibitor (KB228) tested in vitro and in vivo under normoglycemic and diabetic conditions. KB228 administration enhanced glucose sensitivity in chow-fed and obese, diabetic mice that was a result of higher hepatic glucose uptake. Besides improved glucose sensitivity, we have observed further unexpected metabolic rearrangements. KB228 administration increased oxygen consumption that was probably due to the overexpression of uncoupling protein-2 (UCP2) that was observed in animal and cellular models. Furthermore, KB228 treatment induced mammalian target of rapamycin complex 2 (mTORC2) in mice. Our data demonstrate that glucose based GP inhibitors are capable of reducing glucose levels in mice under normo and hyperglycemic conditions. Moreover, these GP inhibitors induce accommodation in addition to GP inhibition - such as enhanced mitochondrial oxidation and mTORC2 signaling – to cope with the glucose influx and increased glycogen deposition in the cells, however the molecular mechanism of accommodation is unexplored

Onkológiai beteg tervezett PET/CT vizsgálata során véletlenszerűen felfedezett COVID–19-betegség.

A koronavírus-betegség 2019 (COVID–19) szakmai irodalma meglehetős gyorsasággal bővül. Adatok jelzik, hogy sokszor nagy az ellentmondás egy-egy beteg esetében a klinikai kép és a radiológiai lelet súlyossága között. Esetismer- tetésünk egy tünetszegény beteg viszonylag súlyosabb radiológiai leleteit részletezi. Az onkológiai alapbetegségben szenvedő, 75 éves nőbetegnél a tervezett, onkológiai indikációval végzett F18-fluoro-dezoxi-glükóz pozitronemisz- sziós tomográfia/komputertomográfia vizsgálat során a tüdőkben incidentálisan COVID–19-re utaló radiomorfoló- giai jeleket azonosítottunk. Azonnali izolációt követően a beteget a megfelelő osztályra helyeztük át, ahol a további vizsgálatok megerősítették a COVID–19 kórisméjét. Esetünk arra hívja fel a figyelmet, hogy járványügyi veszélyhely- zet idején az esendő betegek (magas életkorú, onkológiai betegségben szenvedők) tervezett képalkotó vizsgálata során az elkészült mellkas-CT azonnali kiértékelésének nagy a jelentősége, mert így időben azonosíthatunk a COVID–19 esetleges jelenlétére utaló radiomorfológiai eltéréseket, amelyek alapvetően meghatározzák az aktuális további teendőket

Silencing of PARP2 Blocks Autophagic Degradation

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