A Pyrazolo[3,4-d]pyrimidine compound inhibits Fyn phosphorylation and induces apoptosis in natural killer cell leukemia
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Ilaria Laurenzana1, Antonella Caivano1, Stefania Trino1, Luciana De Luca1, Francesco La Rocca1, Vittorio Simeon1, Cristina Tintori2, Francesca D’Alessio3, Antonella Teramo4, Renato Zambello4, Antonio Traficante5, Maddalena Maietti5, Gianpietro Semenzato4, Silvia Schenone6, Maurizio Botta2, Pellegrino Musto7,*, Luigi Del Vecchio3,8,*
1Laboratory of Preclinical and Translational Research, IRCCS Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy
2Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
3Biotecnologie Avanzate s.c.a.r.l., CEINGE, Napoli, Italy
4Department of Medicine Hematology and Clinical Immunology, Padua University School of Medicine, Padova, Italy
5Unit of Clinical Pathology, IRCCS CROB, Rionero in Vulture (PZ), Italy
6Department of Pharmacy, University of Genoa, Genova, Italy
7Scientific Direction, IRCCS CROB, Rionero in Vulture (PZ), Italy
8Department of Molecular Medicine and Medical Biotechnologies, University of Naples, Napoli, Italy
*These authors contributed equally to this work
Ilaria Laurenzana, email: [email protected]
Keywords: natural killer large granular lymphocyte leukemia, Fyn tyrosine kinase, kinase inhibitor, NK cells
Received: April 06, 2016 Accepted: August 12, 2016 Published: August 22, 2016
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.
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