Ras inhibition amplifies cisplatin sensitivity of human glioblastoma

Samantha Messina, Carlo Leonetti, Giorgia De Gregorio, Valentina Affatigato, Giuseppe Ragona, Luigi Frati, Gabriella Zupi, Angela Santoni, Antonio Porcellini

Research output: Contribution to journalArticle

Abstract

Resistance to chemotherapy is a common feature of malignant gliomas. This resistance is mediated by receptor tyrosine kinase (RTK)-regulated signaling. p21-Ras protein is pivotal in the propagation of the signal originated from many RTKs. Our aim was to investigate whether inhibition of Ras pathway affects the response to cisplatin in malignant gliomas. We found an enhanced sensitivity to cisplatin of two glioblastoma cell lines expressing dominant negative Ras. Moreover, DN-Ras expressing cells, implanted in nude mice, resulted in being extremely sensitive to cisplatin. The growth of all the tumors was significantly inhibited by combining DN-Ras adenovirus infection with cisplatin treatment. The majority of glioma cells expressing DN-Ras underwent apoptosis in response to cisplatin. In vivo, DN-Ras alone did not influence the growth of tumors, suggesting that the effects of Ras-inhibition observed in vitro could not be extrapolated in vivo. The survival signal pathway transduced by Ras was essentially mediated by inhibition of caspase-9 cleavage via PI3K/Akt.

Original languageEnglish
Pages (from-to)493-500
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume320
Issue number2
DOIs
Publication statusPublished - Jul 23 2004

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Keywords

  • Apoptosis
  • Chemotherapy
  • Drug resistance
  • Gene therapy
  • Glioblastoma
  • Ras
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Messina, S., Leonetti, C., De Gregorio, G., Affatigato, V., Ragona, G., Frati, L., Zupi, G., Santoni, A., & Porcellini, A. (2004). Ras inhibition amplifies cisplatin sensitivity of human glioblastoma. Biochemical and Biophysical Research Communications, 320(2), 493-500. https://doi.org/10.1016/j.bbrc.2004.06.003