@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 = {

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.

}, 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 = {

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.

}, 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} } @article {1625, title = {Anti-leukemic activity of dasatinib in both p53(wild-type) and p53(mutated) B malignant cells.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Feb}, pages = {417-22}, abstract = {

The multi-kinase inhibitor dasatinib induced a variable but significant decrease of viability in both p53(wild-type) (EHEB, JVM-2, JVM-3) and p53(mutated) (MEC-1, MEC-2, BJAB) prolymphocytic B leukemic cells, due to a combination of cell cycle block in G1 and apoptosis. Antibody phospho-kinase array analysis revealed that dasatinib inhibited the phosphorylation of various kinases, including ERK1/2 and p38/MAPK as well as of STAT3 transcription factors, in both p53(wild-type) and p53(mutated) cells. Therefore, dasatinib might offer a novel therapeutic strategy not only for p53(wild-type), but also for p53(mutated) B malignancies that have the worst prognosis and urgently need innovative therapeutic approaches.

}, keywords = {Antineoplastic Agents, Apoptosis, B-Lymphocytes, Cell Line, Tumor, Cell Survival, G1 Phase Cell Cycle Checkpoints, Granulocyte Precursor Cells, Humans, Leukemia, Prolymphocytic, B-Cell, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mutation, p38 Mitogen-Activated Protein Kinases, Phosphorylation, Protein Kinase Inhibitors, Pyrimidines, STAT3 Transcription Factor, Thiazoles, Time Factors, Tumor Suppressor Protein p53}, issn = {1573-0646}, doi = {10.1007/s10637-010-9564-6}, author = {Bosco, Raffaella and Rabusin, Marco and Voltan, Rebecca and Celeghini, Claudio and Corallini, Federica and Capitani, Silvano and Secchiero, Paola} }