@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 {3487, title = {NF-κB pathways in hematological malignancies.}, journal = {Cell Mol Life Sci}, volume = {71}, year = {2014}, month = {2014 Jun}, pages = {2083-102}, abstract = {

The nuclear factor κB or NF-κB transcription factor family plays a key role in several cellular functions, i.e. inflammation, apoptosis, cell survival, proliferation, angiogenesis, and innate and acquired immunity. The constitutive activation of NF-κB is typical of most malignancies and plays a major role in tumorigenesis. In this review, we describe NF-κB and its two pathways: the canonical pathway (RelA/p50) and the non-canonical pathway (RelB/p50 or RelB/p52). We then consider the role of the NF-κB subunits in the development and functional activity of B cells, T cells, macrophages and dendritic cells, which are the targets of hematological malignancies. The relevance of the two pathways is described in normal B and T cells and in hematological malignancies, acute and chronic leukemias (ALL, AML, CLL, CML), B lymphomas (DLBCLs, Hodgkin{\textquoteright}s lymphoma), T lymphomas (ATLL, ALCL) and multiple myeloma. We describe the interaction of NF-κB with the apoptotic pathways induced by TRAIL and the transcription factor p53. Finally, we discuss therapeutic anti-tumoral approaches as mono-therapies or combination therapies aimed to block NF-κB activity and to induce apoptosis (PARAs and Nutlin-3).

}, keywords = {Antineoplastic Agents, B-Lymphocytes, Carcinogenesis, Dendritic Cells, Gene Expression Regulation, Neoplastic, Hematologic Neoplasms, Humans, Imidazoles, Macrophages, NF-kappa B, Piperazines, Signal Transduction, T-Lymphocytes, TNF-Related Apoptosis-Inducing Ligand, Transcription Factor RelA, Transcription Factor RelB, Tumor Suppressor Protein p53}, issn = {1420-9071}, doi = {10.1007/s00018-013-1545-4}, author = {Gasparini, Chiara and Celeghini, Claudio and Monasta, Lorenzo and Zauli, Giorgio} } @article {1983, title = {The non-genotoxic activator of the p53 pathway Nutlin-3 shifts the balance between E2F7 and E2F1 transcription factors in leukemic cells.}, journal = {Invest New Drugs}, volume = {31}, year = {2013}, month = {2013 Apr}, pages = {458-60}, abstract = {

The effect of Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, was investigated on the steady-state mRNA levels of the transcription factors E2F1 and E2F7 in a cohort of primary B-chronic lymphocytic leukemia (B-CLL) patient samples (n = 15) and normal peripheral blood mononuclear cells (PBMC). A 24-h treatment with Nutlin-3 significantly down-regulated E2F1 and promoted the concomitant up-regulation of E2F7 in both leukemic and normal cells. Our data suggest that the ability of Nutlin-3 to up-regulate E2F7 likely represents an important molecular determinant in the anti-proliferative activity of Nutlin-3.

}, keywords = {Case-Control Studies, Cells, Cultured, E2F1 Transcription Factor, E2F7 Transcription Factor, Gene Expression Regulation, Leukemic, Humans, Imidazoles, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell, Leukocytes, Mononuclear, Piperazines, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Tumor Suppressor Protein p53}, issn = {1573-0646}, doi = {10.1007/s10637-012-9882-y}, author = {di Iasio, Maria Grazia and Zauli, Giorgio} } @article {1633, title = {The negative prognostic value of TRAIL overexpression in oral squamous cell carcinomas does not preclude the potential therapeutic use of recombinant TRAIL.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Apr}, pages = {810-8}, keywords = {Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Apoptosis, Carcinoma, Squamous Cell, Female, Flow Cytometry, HL-60 Cells, Humans, Immunohistochemistry, Male, Middle Aged, Mouth Neoplasms, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Recombinant Proteins, Risk Assessment, Risk Factors, Survival Analysis, TNF-Related Apoptosis-Inducing Ligand, Tumor Markers, Biological, Up-Regulation, Young Adult}, issn = {1573-0646}, doi = {10.1007/s10637-010-9586-0}, author = {Carinci, Francesco and Monasta, Lorenzo and Rubini, Corrado and Stramazzotti, Daniela and Palmieri, Annalisa and Melloni, Elisabetta and Knowles, Alex and Ronfani, Luca and Zauli, Giorgio and Secchiero, Paola} }