Long-term temozolomide treatment induces marked amino metabolism modifications and an increase in TMZ sensitivity in Hs683 oligodendroglioma cells

Delphine Lamoral-Theys, Marie Le Mercier, Benjamin Le Calvé, Michal A Rynkowski, Céline Bruyère, Christine Decaestecker, Benjamin Haibe-Kains, Gianluca Bontempi, Jacques Dubois, Florence Lefranc, Robert Kiss

Research output: Contribution to journalArticle

Abstract

Gliomas account for more than 50% of all primary brain tumors. The worst prognosis is associated with gliomas of astrocytic origin, whereas gliomas with an oligodendroglial origin offer higher sensitivity to chemotherapy, especially when oligodendroglioma cells display 1p19q deletions. Temozolomide (TMZ) provides therapeutic benefits and is commonly used with radiotherapy in highly malignant astrocytic tumors, including glioblastomas. The actual benefits of TMZ during long-term treatment in oligodendroglioma patients have not yet been clearly defined. In this study, we have investigated the effects of such a long-term TMZ treatment in the unique Hs683 oligodendroglioma model. We have observed increased TMZ sensitivity of Hs683 orthotopic tumors that were previously treated in vitro with months of progressive exposure to increasing TMZ concentrations before being xenografted into the brains of immunocompromised mice. Whole-genome and proteomic analyses have revealed that this increased TMZ sensitivity of Hs683 oligodendroglioma cells previously treated for long periods with TMZ can be explained, at least partly, by a TMZ-induced p38-dependant dormancy state, which in turn resulted in changes in amino acid metabolism balance, in growth delay, and in a decrease in Hs683 oligodendroglioma cell-invasive properties. Thus, long-term TMZ treatment seems beneficial in this Hs683 oligodendroglioma model, which revealed itself unable to develop resistance against TMZ.

Original languageEnglish
Pages (from-to)69-79
Number of pages11
JournalNeoplasia (New York, N.Y.)
Volume12
Issue number1
Publication statusPublished - 2010
Externally publishedYes

Keywords

  • Amino Acids
  • Animals
  • Antineoplastic Agents, Alkylating
  • Apoptosis
  • Blotting, Western
  • Brain Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Dacarbazine
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genomics
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells
  • Oligodendroglioma
  • Proteomics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Xenograft Model Antitumor Assays
  • Journal Article
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Lamoral-Theys, D., Le Mercier, M., Le Calvé, B., Rynkowski, M. A., Bruyère, C., Decaestecker, C., Haibe-Kains, B., Bontempi, G., Dubois, J., Lefranc, F., & Kiss, R. (2010). Long-term temozolomide treatment induces marked amino metabolism modifications and an increase in TMZ sensitivity in Hs683 oligodendroglioma cells. Neoplasia (New York, N.Y.), 12(1), 69-79.