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

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temozolomide
Oligodendroglioma
Therapeutics
Glioma

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

Cite this

Lamoral-Theys, Delphine ; Le Mercier, Marie ; Le Calvé, Benjamin ; Rynkowski, Michal A ; Bruyère, Céline ; Decaestecker, Christine ; Haibe-Kains, Benjamin ; Bontempi, Gianluca ; Dubois, Jacques ; Lefranc, Florence ; Kiss, Robert. / Long-term temozolomide treatment induces marked amino metabolism modifications and an increase in TMZ sensitivity in Hs683 oligodendroglioma cells. In: Neoplasia (New York, N.Y.). 2010 ; Vol. 12, No. 1. pp. 69-79.
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author = "Delphine Lamoral-Theys and {Le Mercier}, Marie and {Le Calv{\'e}}, Benjamin and Rynkowski, {Michal A} and C{\'e}line Bruy{\`e}re and Christine Decaestecker and Benjamin Haibe-Kains and Gianluca Bontempi and Jacques Dubois and Florence Lefranc and Robert Kiss",
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Lamoral-Theys, D, Le Mercier, M, Le Calvé, B, Rynkowski, MA, 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.), vol. 12, no. 1, pp. 69-79.

Long-term temozolomide treatment induces marked amino metabolism modifications and an increase in TMZ sensitivity in Hs683 oligodendroglioma cells. / Lamoral-Theys, Delphine; Le Mercier, Marie; Le Calvé, Benjamin; Rynkowski, Michal A; Bruyère, Céline; Decaestecker, Christine; Haibe-Kains, Benjamin; Bontempi, Gianluca; Dubois, Jacques; Lefranc, Florence; Kiss, Robert.

In: Neoplasia (New York, N.Y.), Vol. 12, No. 1, 2010, p. 69-79.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Long-term temozolomide treatment induces marked amino metabolism modifications and an increase in TMZ sensitivity in Hs683 oligodendroglioma cells

AU - Lamoral-Theys, Delphine

AU - Le Mercier, Marie

AU - Le Calvé, Benjamin

AU - Rynkowski, Michal A

AU - Bruyère, Céline

AU - Decaestecker, Christine

AU - Haibe-Kains, Benjamin

AU - Bontempi, Gianluca

AU - Dubois, Jacques

AU - Lefranc, Florence

AU - Kiss, Robert

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - Amino Acids

KW - Animals

KW - Antineoplastic Agents, Alkylating

KW - Apoptosis

KW - Blotting, Western

KW - Brain Neoplasms

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Dacarbazine

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Genomics

KW - HT29 Cells

KW - Humans

KW - Mice

KW - Mice, Nude

KW - Neoplasm Invasiveness

KW - Neoplastic Stem Cells

KW - Oligodendroglioma

KW - Proteomics

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Time Factors

KW - Xenograft Model Antitumor Assays

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

M3 - Article

VL - 12

SP - 69

EP - 79

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 1

ER -