The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells
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Carolina Simioni1,7,*, Alice Cani1,7,*, Alberto M. Martelli2, Giorgio Zauli3, Ayman A.M. Alameen1,4, Simona Ultimo1, Giovanna Tabellini5, James A. McCubrey6, Silvano Capitani1,7, Luca M. Neri1
1Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
2Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
3Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy
4Department of Chemical Pathology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan
5Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
6Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
7LTTA Center, University of Ferrara, Ferrara, Italy
*These authors have contributed equally to this work
Luca M. Neri, e-mail: [email protected]
Silvano Capitani, e-mail: [email protected]
Keywords: hepatocellular carcinoma, NVP-BGT226, hypoxia, targeted therapies, PI3K/Akt signaling
Received: February 26, 2015 Accepted: May 05, 2015 Published: May 14, 2015
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.
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