Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

Sep 4, 2015Oncotarget

Blocking DNA-repair genes Ercc1 and Mgmt may improve temozolomide treatment in brain tumors

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Abstract

Inhibition of DNA-repair genes could increase cell death in glioma cells by up to 25% when combined with chemotherapy.

Gliomas are the most common primary brain tumors with poor treatment outcomes.
Resistance to chemotherapy, particularly temozolomide, is a significant challenge in glioma treatment.
Targeting the methylation of the Mgmt promoter and other DNA-repair genes may enhance chemotherapy efficacy.
Inhibition of specific DNA-repair genes, including ercc1 and ercc2, was found to sensitize astrocytoma cells to cisplatin and temozolomide.
In vivo results showed reduced glioma tumor growth with siRNA treatment alongside temozolomide absorption.

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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.

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Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

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