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, Luca M. Neri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)17147-17160
Number of pages14
JournalOncotarget
Volume6
Issue number19
Publication statusPublished - 2015

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Keywords

  • Hepatocellular carcinoma
  • Hypoxia
  • NVP-BGT226
  • PI3K/Akt signaling
  • Targeted therapies

ASJC Scopus subject areas

  • Oncology

Cite this

Simioni, C., Cani, A., Martelli, A. M., Zauli, G., Alameen, A. A. M., Ultimo, S., Tabellini, G., McCubrey, J. A., Capitani, S., & Neri, L. M. (2015). The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells. Oncotarget, 6(19), 17147-17160.