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

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dc.contributor.authorSimioni, Carolina
dc.contributor.authorCani, Alice
dc.contributor.authorMartelli, Alberto M.
dc.contributor.authorZauli, Giorgio
dc.contributor.authorAlameen, Ayman A.M.
dc.contributor.authorUltimo, Simona
dc.contributor.authorTabellini, Giovanna
dc.contributor.authorMcCubrey, James A.
dc.contributor.authorCapitani, Silvano
dc.contributor.authorNeri, Luca M.
dc.date.accessioned2016-06-10T19:20:23Z
dc.date.available2016-06-10T19:20:23Z
dc.date.issued2015-07
dc.description.abstractHepatocellular 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 therapyen_US
dc.identifier.citationOncotarget; 6:19 p. 17147-17160en_US
dc.identifier.issn1949-2553
dc.identifier.pmidpmc4627298en_US
dc.identifier.urihttp://hdl.handle.net/10342/5555
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627298/en_US
dc.subjecthepatocellular carcinomaen_US
dc.subjectNVP-BGT226en_US
dc.subjecthypoxiaen_US
dc.subjecttargeted therapiesen_US
dc.subjectPI3K/Akt signalingen_US
dc.titleThe novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cellsen_US
dc.typeArticleen_US
ecu.journal.issue19en_US
ecu.journal.nameOncotargeten_US
ecu.journal.pages17147-17160en_US
ecu.journal.volume6en_US

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