title: A Pyrazolo[3,4-d]pyrimidine compound inhibits Fyn phosphorylation and induces apoptosis in natural killer cell leukemia.
abstract: Natural killer (NK) cell neoplasms are characterized by clonal proliferation of cytotoxic NK cells. Since there is no standard treatment to date, new therapeutic options are needed, especially for NK aggressive tumors. Fyn tyrosine kinase has a key role in different biological processes, such as cell growth and differentiation, being also involved in the pathogenesis of hematologic malignancies. Our previous studies led us to identify 4c pyrazolo[3,4-d]pyrimidine compound capable of inhibiting Fyn activation and inducing apoptosis in different cancer cell lines. Here we investigated the presence of Fyn and the effect of its inhibitor in NK malignant cells. Firstly, we showed Fyn over-expression in NK leukemic cells compared to peripheral blood mononuclear cells from healthy donors. Subsequently, we demonstrated that 4c treatment reduced cell viability, induced caspase 3-mediate apoptosis and cell cycle arrest in NK cells. Moreover, by inhibiting Fyn phosphorylation, 4c compound reduced Akt and P70 S6 kinase activation and changed the expression of genes involved in cell death and survival in NK cells. Our study demonstrated that Fyn is involved in the pathogenesis of NK leukemia and that it could represent a potential target for this neoplasm. Moreover, we proved that Fyn inhibitor pyrazolo[3,4-d]pyrimidine compound, could be a started point to develop new therapeutic agents.
authors: Laboratory of Preclinical and Translational Research, IRCCS Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy.
authors: Ilaria
authors: I
authors: Laurenzana
authors: Laboratory of Preclinical and Translational Research, IRCCS Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy.
authors: Antonella
authors: A
authors: Caivano
authors: Laboratory of Preclinical and Translational Research, IRCCS Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy.
authors: Stefania
authors: S
authors: Trino
authors: Laboratory of Preclinical and Translational Research, IRCCS Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy.
authors: Luciana
authors: L
authors: De Luca
authors: Laboratory of Preclinical and Translational Research, IRCCS Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy.
authors: Francesco
authors: F
authors: La Rocca
authors: Laboratory of Preclinical and Translational Research, IRCCS Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy.
authors: Vittorio
authors: V
authors: Simeon
authors: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
authors: Cristina
authors: C
authors: Tintori
authors: Biotecnologie Avanzate s.c.a.r.l., CEINGE, Napoli, Italy.
authors: Francesca
authors: F
authors: D'Alessio
authors: Department of Medicine Hematology and Clinical Immunology, Padua University School of Medicine, Padova, Italy.
authors: Antonella
authors: A
authors: Teramo
authors: Department of Medicine Hematology and Clinical Immunology, Padua University School of Medicine, Padova, Italy.
authors: Renato
authors: R
authors: Zambello
authors: Unit of Clinical Pathology, IRCCS CROB, Rionero in Vulture (PZ), Italy.
authors: Antonio
authors: A
authors: Traficante
authors: Unit of Clinical Pathology, IRCCS CROB, Rionero in Vulture (PZ), Italy.
authors: Maddalena
authors: M
authors: Maietti
authors: Department of Medicine Hematology and Clinical Immunology, Padua University School of Medicine, Padova, Italy.
authors: Gianpietro
authors: G
authors: Semenzato
authors: Department of Pharmacy, University of Genoa, Genova, Italy.
authors: Silvia
authors: S
authors: Schenone
authors: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
authors: Maurizio
authors: M
authors: Botta
authors: Scientific Direction, IRCCS CROB, Rionero in Vulture (PZ), Italy.
authors: Pellegrino
authors: P
authors: Musto
authors: Biotecnologie Avanzate s.c.a.r.l., CEINGE, Napoli, Italy.|Department of Molecular Medicine and Medical Biotechnologies, University of Naples, Napoli, Italy.
authors: Luigi
authors: L
authors: Del Vecchio
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; C000606692:pyrazolylpyrimidine; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn
keywords: Fyn tyrosine kinase; NK cells; kinase inhibitor; natural killer large granular lymphocyte leukemia