Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study.
Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition.
Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France.|Oxford Functional Neurosurgery and Experimental Neurology, University of Oxford, UK.
Sandra G
SG
Boccard
Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France.
Sandie V
SV
Marand
Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France.
Sandra
S
Geraci
Oxford Functional Neurosurgery and Experimental Neurology, University of Oxford, UK.
Laurie
L
Pycroft
Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France.|CHU de Grenoble, F-38000 Grenoble, France.
François R
FR
Berger
Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France.|CHU de Grenoble, F-38000 Grenoble, France.
Laurent A
LA
Pelletier
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D034622:RNA Interference; D000067492:RNAi Therapeutics; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C071447:ERCC1 protein, human; D004720:Endonucleases; D045643:DNA Repair Enzymes; D002945:Cisplatin; D000077204:Temozolomide
DNA-repair; Temozolomide (TMZ); chemoresistance; glioma; siRNA