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Long-term in vitro treatment of human glioblastoma cells with temozolomide increases resistance in vivo through up-regulation of GLUT transporter and aldo-keto reductase enzyme AKR1C expression.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2010 Sep; Vol. 12 (9), pp. 727-39. - Publication Year :
- 2010
-
Abstract
- Glioblastoma (GBM) is the most frequent malignant glioma. Treatment of GBM patients is multimodal with maximum surgical resection, followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide (TMZ). The present study aims to identify genes implicated in the acquired resistance of two human GBM cells of astrocytic origin, T98G and U373, to TMZ. Resistance to TMZ was induced by culturing these cells in vitro for months with incremental TMZ concentrations up to 1 mM. Only partial resistance to TMZ has been achieved and was demonstrated in vivo in immunocompromised mice bearing orthotopic U373 and T98G xenografts. Our data show that long-term treatment of human astroglioma cells with TMZ induces increased expression of facilitative glucose transporter/solute carrier GLUT/SLC2A family members, mainly GLUT-3, and of the AKR1C family of proteins. The latter proteins are phase 1 drug-metabolizing enzymes involved in the maintenance of steroid homeostasis, prostaglandin metabolism, and metabolic activation of polycyclic aromatic hydrocarbons. GLUT-3 has been previously suggested to exert roles in GBM neovascularization processes, and TMZ was found to exert antiangiogenic effects in experimental gliomas. AKR1C1 was previously shown to be associated with oncogenic potential, with proproliferative effects similar to AKR1C3 in the latter case. Both AKR1C1 and AKR1C2 proteins are involved in cancer pro-proliferative cell chemoresistance. Selective targeting of GLUT-3 in GBM and/or AKR1C proteins (by means of jasmonates, for example) could thus delay the acquisition of resistance to TMZ of astroglioma cells in the context of prolonged treatment with this drug.
- Subjects :
- Alcohol Oxidoreductases metabolism
Aldehyde Reductase
Aldo-Keto Reductases
Animals
Antineoplastic Agents, Alkylating pharmacology
Antineoplastic Agents, Alkylating therapeutic use
Brain Neoplasms metabolism
Brain Neoplasms pathology
Cell Culture Techniques
Cell Line, Tumor
Dacarbazine adverse effects
Dacarbazine pharmacology
Dacarbazine therapeutic use
Female
Gene Expression Regulation, Neoplastic drug effects
Glioblastoma metabolism
Glioblastoma pathology
Glucose Transport Proteins, Facilitative metabolism
HT29 Cells
Humans
Mice
Mice, Nude
Temozolomide
Time Factors
Up-Regulation drug effects
Up-Regulation genetics
Xenograft Model Antitumor Assays
Alcohol Oxidoreductases genetics
Brain Neoplasms genetics
Dacarbazine analogs & derivatives
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Glioblastoma genetics
Glucose Transport Proteins, Facilitative genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 12
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 20824049
- Full Text :
- https://doi.org/10.1593/neo.10526