title: New pyrazolo-[3,4-d]-pyrimidine derivative Src kinase inhibitors lead to cell cycle arrest and tumor growth reduction of human medulloblastoma cells.
abstract: Medulloblastoma is the most common malignant brain tumor in children, and despite improvements in the overall survival rate, it still lacks an effective treatment. Src plays an important role in cancer, and recently high Src activity was documented in medulloblastoma. In this report, we examined the effects of novel pyrazolo-[3,4-d]-pyrimidine derivative Src inhibitors in medulloblastoma. By MTS assay, we showed that the pyrimidine derivatives indicated as S7, S29, and SI163 greatly reduce the growth rate of medulloblastoma cells by inhibiting Src phosphorylation, compared with HT22 non-neoplastic nerve cells. These compounds also halt cells in the G(2)/M phase, and this effect likely occurs through the regulation of cdc2 and CDC25C phosphorylation, as shown by Western blot. Moreover, the exposure to pyrimidine derivatives induces apoptosis, assayed by the supravital propidium iodide assay, through modulation of the apoptotic proteins Bax and Bcl2, and inhibits tumor growth in vivo in a mouse model. Notably, S7, S29, and SI163 show major inhibitory effects on medulloblastoma cell growth compared with the chemotherapeutic agents cisplatin and etoposide. In conclusion, our results suggest that S7, S29, and SI163 could be novel attractive candidates for the treatment of medulloblastoma or tumors characterized by high Src activity.
authors.affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, 1900 North 12th St., Philadelphia, PA 19122, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rossi
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.forename: Martina
authors.initials: M
authors.lastname: Cozzi
authors.forename: Valentina
authors.initials: V
authors.lastname: Caracciolo
authors.forename: Francesca
authors.initials: F
authors.lastname: Pentimalli
authors.forename: Andrew
authors.initials: A
authors.lastname: Puca
authors.forename: Biagio
authors.initials: B
authors.lastname: Pucci
authors.forename: Raffaele
authors.initials: R
authors.lastname: La Montagna
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019061:src-Family Kinases