@article {7726,
	title = {The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells.},
	journal = {Oncotarget},
	volume = {6},
	year = {2015},
	month = {2015 Jul 10},
	pages = {17147-60},
	abstract = {<p>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.</p>},
	issn = {1949-2553},
	doi = {10.18632/oncotarget.3940},
	author = {Simioni, Carolina and Cani, Alice and Martelli, Alberto M and Zauli, Giorgio and Alameen, Ayman A M and Ultimo, Simona and Tabellini, Giovanna and McCubrey, James A and Capitani, Silvano and Neri, Luca M}
}
@article {7728,
	title = {Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia.},
	journal = {Oncotarget},
	volume = {6},
	year = {2015},
	month = {2015 Mar 30},
	pages = {6597-610},
	abstract = {<p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder in which chemotherapy resistance and refractory relapses occur, with a poorer prognostic outcome.Constitutively active PI3K/Akt/mTOR pathway is a common feature of T-ALL upregulating cell proliferation, survival and drug resistance. This pathway is currently under clinical trials with small molecules inhibitors (SMI).To verify whether a multi-inhibition treatment against Akt protein could enhance the efficacy of individual drug administration and overcome drug resistance as well as to obtain a decrease in single drug concentration, we tested on T-ALL cell lines the effects of combined treatments with three Akt inhibitors with different mode of action, GSK690693, MK-2206 and Perifosine.In cells with hyperactivated Akt, combined administration of the drugs displayed a significant synergistic and cytotoxic effect and affected PI3K/Akt/mTOR pathway at much lower concentration than single drug use. Highest synergistic effect for full inhibition of Akt was also related to the timing of every drug administration. Furthermore the triple treatment had greater efficacy in inducing cell cycle arrest in G0/G1 phase and both apoptosis and autophagy.Targeting Akt as a key protein of PI3K/Akt/mTOR pathway with multiple drugs might represent a new and promising pharmacological strategy for treatment of T-ALL patients.</p>},
	issn = {1949-2553},
	doi = {10.18632/oncotarget.3260},
	author = {Cani, Alice and Simioni, Carolina and Martelli, Alberto M and Zauli, Giorgio and Tabellini, Giovanna and Ultimo, Simona and McCubrey, James A and Capitani, Silvano and Neri, Luca M}
}
