New pyrazolo-[3,4-d]-pyrimidine derivative Src kinase inhibitors lead to cell cycle arrest and tumor growth reduction of human medulloblastoma cells

Alessandra Rossi, Silvia Schenone, Adriano Angelucci, Martina Cozzi, Valentina Caracciolo, Francesca Pentimalli, Andrew Puca, Biagio Pucci, Raffaele La Montagna, Mauro Bologna, Maurizio Botta, Antonio Giordano

Research output: Contribution to journalArticlepeer-review

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 G2/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.

Original languageEnglish
Pages (from-to)2881-2892
Number of pages12
JournalFASEB Journal
Volume24
Issue number8
DOIs
Publication statusPublished - Aug 2010

Keywords

  • Apoptosis
  • Brain tumors
  • Cancer therapy
  • cdc2
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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