Effect of lomeguatrib–temozolomide combination on MGMT promoter methylation and expression in primary glioblastoma tumor cells

Mar 23, 2013Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine

Lomeguatrib and temozolomide treatment and its impact on gene control and activity in primary brain tumor cells

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

The combination of lomeguatrib and temozolomide decreased MGMT expression in primary glioblastoma cell cultures.

Lomeguatrib, an MGMT inactivator, was tested in combination with temozolomide for its effect on glioblastoma cells.
The combination treatment resulted in increased expression of p53, indicating a potential response to stress or damage.
Apoptosis was induced and DNA fragmentation increased in the cells treated with lomeguatrib and temozolomide.
No changes were observed in MGMT methylation following the combination treatment.
Sensitivity to the lomeguatrib-temozolomide combination varied among different primary glioblastoma cells and glioma cell lines, potentially linked to MGMT methylation structure.

AI simplified

Temozolomide (TMZ) is commonly used in the treatment of glioblastoma (GBM). The MGMT repair enzyme (O (6)-methylguanine-DNA methyltransferase) is an important factor causing chemotherapeutic resistance. MGMT prevents the formation of toxic effects of alkyl adducts by removing them from the DNA. Therefore, MGMT inhibition is an interesting therapeutic approach to circumvent TMZ resistance. The aim of the study was to investigate the effect of the combination of lomeguatrib (an MGMT inactivator) with TMZ, on MGMT expression and methylation. Primary cell cultures were obtained from GBM tumor tissues. The sensitivity of primary GBM cell cultures and GBM cell lines to TMZ, and to the combination of TMZ and lomeguatrib, was determined by a cytotoxicity assay (MTT). MGMT and p53 expression, and MGMT methylation were investigated after drug application. In addition, the proportion of apoptotic cells and DNA fragmentation was analyzed. The combination of TMZ and lomeguatrib in primary GBM cell cultures and glioma cell lines decreased MGMT expression, increased p53 expression, and did not change MGMT methylation. Moreover, apoptosis was induced and DNA fragmentation was increased in cells. In addition, we also showed that lomeguatrib-TMZ combination did not have any effect on the cell cycle. Finally, we determined that the sensitivity of each primary GBM cells and glioma cell lines to the lomeguatrib-TMZ combination was different and significantly associated with the structure of MGMT methylation. Our study suggests that lomeguatrib can be used with TMZ for GBM treatment, although further clinical studies will be needed so as to determine the feasibility of this therapeutic approach.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text (HTML) ↗View full text ↗

Effect of lomeguatrib–temozolomide combination on MGMT promoter methylation and expression in primary glioblastoma tumor cells

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief