Oncotarget

Research Papers:

The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells

Carolina Simioni _, Alice Cani, Alberto M. Martelli, Giorgio Zauli, Ayman A.M. Alameen, Simona Ultimo, Giovanna Tabellini, James A. McCubrey, Silvano Capitani and Luca M. Neri

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Oncotarget. 2015; 6:17147-17160. https://doi.org/10.18632/oncotarget.3940

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Abstract

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

Correspondence to:

Luca M. Neri, e-mail: luca.neri@unife.it

Silvano Capitani, e-mail: silvano.capitani@unife.it

Keywords: hepatocellular carcinoma, NVP-BGT226, hypoxia, targeted therapies, PI3K/Akt signaling

Received: February 26, 2015     Accepted: May 05, 2015     Published: May 14, 2015

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.


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