Abstract

Temozolomide (TMZ) is an oral alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma (GBM). Despite that high TMZ potential, progression of disease and recurrence are still observed. Therefore a better understanding of the mechanism of action of this drug is necessary and may allow more durable benefit from its anti-glioma properties. Using nucleotide post-labelling method and separation on thin-layer chromatography we measured of global changes of 5-methylcytosine (m5C) in DNA of glioma cells treated with TMZ. Although m5C is not a product of TMZ methylation reaction of DNA, we analysed the effects of the drug action on different glioma cell lines through global changes at the level of the DNA main epigenetic mark. The first effect of TMZ action we observed is DNA hypermethylation followed by global demethylation. Therefore an increase of DNA methylation and down regulation of some genes expression can be ascribed to activation of DNA methyltransferases (DNMTs). On the other hand hypomethylation is induced by oxidative stress and causes uncontrolled expression of pathologic protein genes. The results of brain tumours treatment with TMZ suggest the new mechanism of modulation epigenetic marker in cancer cells. A high TMZ concentration induced a significant increase of m5C content in DNA in the short time, but a low TMZ concentration at longer time hypomethylation is observed for whole range of TMZ concentrations. Therefore TMZ administration with low doses of the drug and short time should be considered as optimal therapy.

Highlights

  • Malignant gliomas are the most prevalent type of primary brain tumour in adults

  • The highest decrease of R one can observe at the highest TMZ concentration (1000 μM) and 48 h (Fig 4)

  • Resistance to temozolomide via DNA repair mechanism based on O6 methylguanosine methyltransferases remains a significant issue for the successful treatment of patients with malignant glioma

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Summary

Introduction

Malignant gliomas are the most prevalent type of primary brain tumour in adults. They constitute approximately 50% of all central nervous system tumors [1]. Glioblastoma multiforme (GBM) is the most lethal subtype with a mean patient survival of 8–12 months from time of diagnosis [2,3]. The conventional therapy for GBM includes surgery followed by radiotherapy and chemotherapy [4]. DNA alkylation reagents are the oldest class of anti-cancer drugs. They are currently in use, and remain important for the treatment of various types of cancers including brain tumours [5,6]. Alkylating agents damage DNA by formation of different small or PLOS ONE | DOI:10.1371/journal.pone.0136669 August 26, 2015

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