Long-term temozolomide treatment induces marked amino metabolism modifications and an increase in TMZ sensitivity in Hs683 oligodendroglioma cells.
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.
Lamoral-Theys
Delphine
D
Laboratoire de Chimie Bioanalytique, Toxicologie et Chimie Physique Appliquée, Brussels, Belgium.
Le Mercier
Marie
M
Le Calvé
Benjamin
B
Rynkowski
Michal A
MA
Bruyère
Céline
C
Decaestecker
Christine
C
Haibe-Kains
Benjamin
B
Bontempi
Gianluca
G
Dubois
Jacques
J
Lefranc
Florence
F
Kiss
Robert
R
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics / Q000379:methods; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009837:Oligodendroglioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000596:Amino Acids; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide