title: The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells.
abstract: Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide and its advanced status is frequently resistant to conventional chemotherapeutic agents and radiation. We evaluated the cytotoxic effect of the orally bioavailable dual PI3K/mTOR inhibitor, NVP-BGT226, on a panel of HCC cell lines, since hyperactivated PI3K/Akt/mTOR signaling pathway could represent a biomolecular target for Small Inhibitor Molecules in this neoplasia. We analyzed the drug activity in both normoxia and hypoxia conditions, the latter playing often a relevant role in the induction of chemoresistance and angiogenesis.In normoxia NVP-BGT226 caused cell cycle arrest in the G0/G1 phase of the cell cycle, induced apoptosis and autophagy at low concentrations. Interestingly the drug inactivated p-Akt and p-S6 at < 10 nM concentration.In hypoxia NVP-BGT226 maintained its cytotoxic efficacy at the same concentration as documented by MTT assays and Western blot analysis. Moreover, the drug showed in hypoxia inhibitory properties against angiogenesis by lowering the expression of the transcription factor HIF-1α and of VEGF.Our results indicate that NVP-BGT226 has a potent cytotoxic effect on HCC cell lines also in hypoxia condition, thus emerging as a potential candidate for cancer treatment in HCC targeted therapy.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Simioni
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Cani
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|Department of Chemical Pathology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan.
authors.forename: Ayman A M
authors.initials: AA
authors.lastname: Alameen
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ultimo
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tabellini
authors.affiliation: Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Luca M
authors.initials: LM
authors.lastname: Neri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: NVP-BGT226; PI3K/Akt signaling; hepatocellular carcinoma; hypoxia; targeted therapies