@article {7767, title = {Serum TRAIL levels increase shortly after insulin therapy and metabolic stabilization in children with type 1 diabetes mellitus.}, journal = {Acta Diabetol}, volume = {52}, year = {2015}, month = {2015 Oct}, pages = {1003-6}, issn = {1432-5233}, doi = {10.1007/s00592-015-0731-2}, author = {Tornese, Gianluca and Tisato, Veronica and Monasta, Lorenzo and Vecchi Brumatti, Liza and Zauli, Giorgio and Secchiero, Paola} } @article {3581, title = {Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3.}, journal = {Oncotarget}, volume = {5}, year = {2014}, month = {2014 Jun 30}, pages = {4347-60}, abstract = {

The anti-leukemic activity of the mitochondria-targeting small molecule sodium dichloroacetate (DCA), used alone and in association with the small molecule inhibitor of the p53/MDM2 interaction Nutlin-3, was analyzed in primary B-chronic lymphocytic leukemia (B-CLL) samples (n=22), normal peripheral blood cells (n=10) and in p53wild-type EHEB, JVM-2, JVM-3 B lymphoblastoid cell lines. DCA exhibited a dose-dependent anti-leukemic activity in both primary B-CLL and B leukemic cell lines with a functional p53 status and showed a synergistic cytotoxic activity when used in combination with Nutlin-3. At the molecular level, DCA positively regulated p53 activity, as documented by post-transcriptional modifications of p53 protein and synergized with Nutlin-3 in increasing the expression of the p53-target genes MDM2, PUMA, TIGAR and in particular p21. The potential role of p21 in mediating the DCA+Nutlin-3 anti-leukemic activity was underscored in knocking-down experiments. Indeed, transfection of leukemic cells with p21 siRNAs significantly decreased the DCA+Nutlin-3-induced cytotoxicity. Taken together, our data emphasize that DCA is a molecule that merits to be further evaluated as a chemotherapeutic agent for B-CLL, likely in combination with other therapeutic compounds.

}, keywords = {Aged, Aged, 80 and over, Dichloroacetic Acid, Drug Synergism, Female, Humans, Imidazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperazines, Tumor Suppressor Protein p53}, issn = {1949-2553}, author = {Agnoletto, Chiara and Melloni, Elisabetta and Casciano, Fabio and Rigolin, Gian Matteo and Rimondi, Erika and Celeghini, Claudio and Brunelli, Laura and Cuneo, Antonio and Secchiero, Paola and Zauli, Giorgio} } @article {3527, title = {Soluble TRAIL is present at high concentrations in seminal plasma and promotes spermatozoa survival.}, journal = {Reproduction}, volume = {148}, year = {2014}, month = {2014 Aug}, pages = {191-8}, abstract = {

The expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL(TNFSF10)) and of its receptors (TRAILR1, TRAILR2, TRAILR3, and TRAILR4) have been documented in testis, but the presence of soluble TRAIL in seminal fluid, as well as the potential physiopathological role of the TRAIL/TRAILR system in spermatozoa, has not been previously investigated. Male donors (n=123) among couples presenting for infertility evaluation were consecutively enrolled in this study. The presence of soluble TRAIL was analyzed in seminal samples by ELISA, while the surface expression of TRAIL receptors was investigated by flow cytometry. High levels of soluble TRAIL were detected in seminal plasma (median, 11 621 pg/ml and mean{\textpm}s.d., 13 371{\textpm}8367 pg/ml) and flow cytometric analysis revealed a variable expression of TRAIL receptors in the sperm cellular fraction among different subjects. In addition, the effect of physiologically relevant concentrations of recombinant TRAIL was investigated on survival and motility of spermatozoa. Of interest, the in vitro exposure of capacitated spermatozoa to recombinant TRAIL (10 ng/ml) significantly preserved their overall survival. Therefore, the present study demonstrates for the first time the presence of elevated levels of the anti-inflammatory cytokine TRAIL in seminal fluids. Moreover, the demonstration that recombinant TRAIL promotes spermatozoa survival after capacitation suggests potential therapeutic implications.

}, keywords = {Adult, Apoptosis, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Infertility, Male, Male, Receptors, TNF-Related Apoptosis-Inducing Ligand, Semen, Sperm Capacitation, Sperm Motility, Spermatozoa, TNF-Related Apoptosis-Inducing Ligand}, issn = {1741-7899}, doi = {10.1530/REP-14-0144}, author = {Zauli, Giorgio and Celeghini, Claudio and Monasta, Lorenzo and Martinelli, Monica and Luppi, Stefania and Gonelli, Arianna and Grill, Vittorio and Ricci, Giuseppe and Secchiero, Paola} } @article {1969, title = {Simultaneous determination of multiple cytokines reveals a pro-inflammatory and pro-angiogenic signature after major cardiothoracic surgery: potential role of C-reactive protein.}, journal = {Cytokine}, volume = {60}, year = {2012}, month = {2012 Dec}, pages = {593-5}, keywords = {C-Reactive Protein, Coronary Artery Bypass, Cytokines, Humans, Inflammation, Macrophages, Neovascularization, Physiologic, Risk Factors}, issn = {1096-0023}, doi = {10.1016/j.cyto.2012.08.017}, author = {Tisato, Veronica and Monasta, Lorenzo and Biolo, Gianni and Donatelli, Francesco and Secchiero, Paola and Zauli, Giorgio} } @article {1903, title = {SOCS1 is significantly up-regulated in Nutlin-3-treated p53wild-type B chronic lymphocytic leukemia (B-CLL) samples and shows an inverse correlation with miR-155.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Dec}, pages = {2403-6}, abstract = {

The basal SOCS1 mRNA levels were significantly lower in p53(mutated) BJAB and MAVER leukemic cell lines with respect to p53(wild-type) SKW6.4 and JVM-2 leukemic cell lines, p53(wild-type) primary B chronic lymphocytic leukemia (B-CLL) cells and primary normal peripheral blood mononuclear cells (PBMC). Moreover, the MDM2 small molecule inhibitor Nutlin-3 significantly increased the levels of SOCS1 mRNA in both primary p53(wild-type) B-CLL cells as well as in p53(wild-type) B leukemic cell lines, but not in p53(mutated) B leukemic cell lines nor in primary PBMC. Of note, a significant inverse correlation was observed between SOCS1 mRNA and miR-155 levels in Nutlin-3-treated primary B-CLL cells and PBMC, suggesting that the miRNA-155/SOCS1 axis represents a potentially important therapeutic target of Nutlin-3 in B-CLL.

}, keywords = {Cell Line, Tumor, Cells, Cultured, Down-Regulation, Humans, Imidazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Leukocytes, Mononuclear, MicroRNAs, Piperazines, Suppressor of Cytokine Signaling Proteins, Tumor Suppressor Protein p53, Up-Regulation}, issn = {1573-0646}, doi = {10.1007/s10637-011-9786-2}, author = {di Iasio, Maria Grazia and Norcio, Alessia and Melloni, Elisabetta and Zauli, Giorgio} } @article {1964, title = {Soluble TRAIL is elevated in recurrent miscarriage and inhibits the in vitro adhesion and migration of HTR8 trophoblastic cells.}, journal = {Hum Reprod}, volume = {27}, year = {2012}, month = {2012 Oct}, pages = {2941-7}, abstract = {

STUDY QUESTION: What is the potential physiopathological role of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in recurrent miscarriage (RM), characterized by at least three consecutive pregnancy losses.

SUMMARY ANSWER: The levels of serum TRAIL immediately after miscarriage in RM patients are significantly elevated with respect to that in first-trimester normal pregnant women, and recombinant TRAIL inhibits the adhesion and migration of HTR8 trophoblastic cells in vitro.

WHAT IS KNOWN ALREADY: Both TRAIL and its trans-membrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3~and TRAIL-R4) have been documented in the placenta, but their physiopathological role is incompletely understood.

STUDY DESIGN, SIZE, DURATION: The study populations consisted of RM patients (n = 80) and first-trimester normal pregnant women (n = 80). Blood samples were obtained within 24 h after abortion (RM) or at gestational 12-week (normal pregnant women). As additional controls, third-trimester normal pregnant women (n = 28) were examined before (within 72 h) and after (within 24 h) partum.

PARTICIPANTS/MATERIALS, SETTING, METHODS: The concentrations of TRAIL were analysed in serum samples by ELISA. In parallel, the effect of soluble recombinant TRAIL (0.1-1000 ng/ml) was analysed on the survival of primary extravillus trophoblasts (EVTs) and on the survival, proliferation, adhesion and migration of trophoblastic HTR8 cells.

MAIN RESULTS AND THE ROLE OF CHANCE: The circulating levels of TRAIL in RM women (median: 52.5 pg/ml; mean and SD: 55.5 {\textpm} 24.4 pg/ml) were significantly higher with respect to first-trimester normal pregnant women (median: 44.9 pg/ml; mean and SD: 47 {\textpm} 15.1 pg/ml) and third-trimester normal pregnant women, as assessed before (median: 45.1 pg/ml; mean and SD: 46 {\textpm} 12.4 pg/ml) and after partum (median: 35.4 pg/ml; mean and SD: 38 + 17.5 pg/ml). Both primary EVT and HTR8 cells expressed detectable levels of TRAIL death receptors, but exposure to soluble recombinant TRAIL did not induce cell death of trophoblastic cells. On the other hand, TRAIL dose-dependently inhibited the adhesion of HTR8 cells to decidual endothelial cells (DEC) as well as the migration of HTR8 in transwell assays using either fibronectin or DEC.

LIMITATIONS, REASONS FOR CAUTION: Although this study suggests that TRAIL might have a pathogenic role in RM by inhibiting both the adhesion and migration capabilities of first trimester trophoblastic cells, there is a possibility that the elevated serum levels of TRAIL in RM are not cause but rather the result of RM.

WIDER IMPLICATIONS OF THE FINDINGS: Our current findings together with data of other authors suggest that circulating TRAIL should be further analysed as a potential important biomarker in different physiopathological settings.

STUDY FUNDING/COMPETING INTEREST(S): This study was funded by FIRB projects (RBAP11Z4Z9_002 to Giorgio Zauli and RBAP10447J_002 to Paola Secchiero). The authors have no competing interests to declare.

}, keywords = {Abortion, Habitual, Apoptosis, Cell Adhesion, Cell Line, Cell Movement, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Female, Humans, Pregnancy, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand, Trophoblasts}, issn = {1460-2350}, doi = {10.1093/humrep/des289}, author = {Agostinis, Chiara and Bulla, Roberta and Tisato, Veronica and De Seta, Francesco and Alberico, Salvatore and Secchiero, Paola and Zauli, Giorgio} } @article {1926, title = {The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status.}, journal = {Haematologica}, volume = {97}, year = {2012}, month = {2012 Nov}, pages = {1722-30}, abstract = {

BACKGROUND: Both the multi-kinase inhibitor sorafenib and the small molecule inhibitor of the MDM2/p53 interaction, nutlin-3, used alone, have shown promising anti-leukemic activity in acute myeloid leukemia cells. Thus, in this study we investigated the effect of the combination of sorafenib plus nutlin-3 in acute myeloid leukemia.

DESIGN AND METHODS: Primary acute myeloid leukemia blasts (n=13) and FLT3(wild-type)/p53(wild-type) (OCI-AML3), FLT3(mutated)/p53(wild-type) (MOLM), FLT3(mutated)/p53(mutated) (MV4-11), FLT3(wild-type)/p53(deleted) (HL60) or FLT3(wild-type)/p53(mutated) (NB4) acute myeloid cell lines were exposed to sorafenib, used alone or in association with nutlin-3 at a 1:1 ratio, in a range of clinically achievable concentrations (1-10 μM). Induction of apoptosis and autophagy was evaluated by transmission electron microscopy and by specific flow cytometry analyses. The levels of Mcl-1, p53 and Bak proteins were analyzed by western blotting. Knock-down of Bax and Bak gene expression was performed in transfection experiments with specific short interfering RNA.

RESULTS: The sorafenib+nutlin-3 drug combination exhibits synergistic cytotoxicity in primary acute myeloid leukemia blasts and in acute myeloid leukemia cell lines with maximal cytotoxicity in FLT3(mutated) MV4-11 and MOLM, followed by the FLT3(wild-type) OCI-AML3, HL60 and NB4 cell lines. The cytotoxic activity of sorafenib+nutlin-3 was characterized by an increase of both apoptosis and autophagy. Moreover, Bax and Bak showed prominent roles in mediating the decrease of cell viability in response to the drug combination in p53(wild-type) OCI-AML3 and p53(deleted) HL-60 cells, respectively, as demonstrated in transfection experiments performed with specific short interfering RNA.

CONCLUSIONS: Our data demonstrate that acute myeloid leukemia cells show a variable but overall good susceptibility to the innovative therapeutic combination of sorafenib+nutlin-3, which differentially involves the pro-apoptotic Bcl-2 family members Bax and Bak in p53(wild-type) and p53(deleted) cells.

}, keywords = {Antineoplastic Agents, Drug Synergism, Female, fms-Like Tyrosine Kinase 3, HL-60 Cells, Humans, Imidazoles, Leukemia, Myeloid, Acute, Male, Niacinamide, Phenylurea Compounds, Piperazines, Tumor Suppressor Protein p53}, issn = {1592-8721}, doi = {10.3324/haematol.2012.062083}, author = {Zauli, Giorgio and Celeghini, Claudio and Melloni, Elisabetta and Voltan, Rebecca and Ongari, Manuele and Tiribelli, Mario and di Iasio, Maria Grazia and Lanza, Francesco and Secchiero, Paola} } @article {1814, title = {State of art and recent developments of anti-cancer strategies based on TRAIL.}, journal = {Recent Pat Anticancer Drug Discov}, volume = {7}, year = {2012}, month = {2012 May 1}, pages = {207-17}, abstract = {

Multicellular organisms require apoptosis whereby the human body eliminates unnecessary and/or damaged cells. Apoptosis, or programmed cell death, can indeed be considered as a constitutive anti-cancer mechanism that seems to be defective in more than 50\% of cancers. Molecular insights on the biology of the apoptotic process have led to the development of new anti-cancer strategies aiming at recovering and stimulating this process. Preclinical and clinical studies of our and other groups have demonstrated that targeting the extrinsic apoptotic pathway by various death receptors agonists is a safe and effective anti-cancer strategy, which thus may become a new cornerstone of cancer therapy. Here, we review the most recent acquisitions and patents on TRAIL or TRAIL mimetics, as well as the combination therapies that could be used with them.

}, keywords = {Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Clinical Trials as Topic, Humans, Mice, Neoplasms, Receptors, Death Domain, TNF-Related Apoptosis-Inducing Ligand}, issn = {2212-3970}, author = {Bernardi, Stella and Secchiero, Paola and Zauli, Giorgio} }