Mechanisms of BSO (L-buthionine-S,R-sulfoximine)-induced cytotoxic effects in neuroblastoma

Barbara Marengo, Chiara De Ciucis, Daniela Verzola, Vito Pistoia, Lizzia Raffaghello, Stefania Patriarca, Emanuela Balbis, Nicola Traverso, Damiano Cottalasso, Maria A. Pronzato, Umberto M. Marinari, Cinzia Domenicotti

Research output: Contribution to journalArticle

Abstract

Glutathione (GSH) depletion is widely used to sensitize cells to anticancer treatment inducing the progression of programmed cell death and overcoming chemoresistance. It has been reported that neuroblastoma cells with MYCN amplification are unable to start TRAIL-dependent death and MYCN, in concert with cytotoxic drugs, efficiently induces the mitochondrial pathway of apoptosis through oxidative mechanisms. In this study, we show that GSH loss induced by L-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH biosynthesis, leads to overproduction of reactive oxygen species (ROS) and triggers apoptosis of MYCN-amplified neuroblastoma cells. BSO susceptibility of SK-N-BE-2C, a representative example of MYCN-amplified cells, has been attributed to stimulation of total SOD activity in the absence of changes in the level and the activity of catalase. Therefore, the unbalanced intracellular redox milieu has been demonstrated to be critical for the progression of neuroblastoma cell death that was efficiently prevented by antioxidants and rottlerin. These results describe a novel pathway of apoptosis dependent on ROS formation and PKC-delta activation and independent of p53, bcl-2, and bax levels; the selective redox modulation of PKC-delta might be suggested as a potential strategy for sensitizing MYCN-amplified cells to therapeutic approaches.

Original languageEnglish
Pages (from-to)474-482
Number of pages9
JournalFree Radical Biology and Medicine
Volume44
Issue number3
DOIs
Publication statusPublished - Feb 1 2008

Keywords

  • Apoptosis
  • L-Buthionine-S,R-sulfoximine
  • MYCN
  • Neuroblastoma
  • Protein kinase C delta
  • Reactive oxygen species

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

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