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BACKGROUND/AIM: The alkylating agent, temozolomide (TMZ), is considered the standard-of-care for high-grade astrocytomas -known as glioblastoma multiforme (GBM)- an aggressive type of tumor with poor prognosis. The therapeutic benefit of TMZ is attributed to formation of DNA adducts involving the methylation of purine bases in DNA. We investigated the effects of TMZ on arginine and lysine amino acids, histone H3 peptides and histone H3 proteins.
MATERIALS AND METHODS: Chemical modification of amino acids, histone H3 peptide and protein by TMZ was performed in phosphate buffer at physiological pH. The reaction products were examined by mass spectrometry and western blot analysis.
RESULTS: Our results showed that TMZ following conversion to a methylating cation, can methylate histone H3 peptide and histone H3 protein, suggesting that TMZ exerts its anticancer activity not only through its interaction with DNA, but also through alterations of protein post-translational modifications.
CONCLUSION: The possibility that TMZ can methylate histones involved with epigenetic regulation of protein indicates a potentially unique mechanism of action. The study will contribute to the understanding the anticancer activity of TMZ in order to develop novel targeted molecular strategies to advance the cancer treatment.
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Ballesta,
Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic models for personalized medicine: application to temozolomide in brain tumors.
2014, Pubmed
Ballesta,
Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic models for personalized medicine: application to temozolomide in brain tumors.
2014,
Pubmed
Berger,
The complex language of chromatin regulation during transcription.
2007,
Pubmed
Bulau,
Quantitative assessment of arginine methylation in free versus protein-incorporated amino acids in vitro and in vivo using protein hydrolysis and high-performance liquid chromatography.
2006,
Pubmed
Campbell,
On performing simultaneous electron transfer dissociation and collision-induced dissociation on multiply protonated peptides in a linear ion trap.
2009,
Pubmed
Chatterjee,
N-methylation of peptides and proteins: an important element for modulating biological functions.
2013,
Pubmed
Denny,
NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA.
1994,
Pubmed
Etcheverry,
DNA methylation in glioblastoma: impact on gene expression and clinical outcome.
2010,
Pubmed
Gerson,
Clinical relevance of MGMT in the treatment of cancer.
2002,
Pubmed
Højfeldt,
Histone lysine demethylases as targets for anticancer therapy.
2013,
Pubmed
Huse,
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma.
2010,
Pubmed
Jones,
Targeting the cancer epigenome for therapy.
2016,
Pubmed
Kaina,
DNA repair in resistance to alkylating anticancer drugs.
2002,
Pubmed
Kim,
Aberrant CpG islands hypermethylation profiles in malignant gliomas.
2014,
Pubmed
Kokkinakis,
Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide.
2001,
Pubmed
Koukourakis,
Temozolomide with radiation therapy in high grade brain gliomas: pharmaceuticals considerations and efficacy; a review article.
2009,
Pubmed
Lilja,
Like a rolling histone: epigenetic regulation of neural stem cells and brain development by factors controlling histone acetylation and methylation.
2013,
Pubmed
Louis,
The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.
2016,
Pubmed
Magerl,
H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1.
2010,
Pubmed
Manuyakorn,
Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704.
2010,
Pubmed
Natsume,
Epigenetic aberrations and therapeutic implications in gliomas.
2010,
Pubmed
Okitsu,
DNA methylation dictates histone H3K4 methylation.
2007,
Pubmed
Rabik,
Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy.
2006,
Pubmed
Rothbart,
Interpreting the language of histone and DNA modifications.
2014,
Pubmed
Schubert,
1 Protein Methyltransferases: Their Distribution Among the Five Structural Classes of AdoMet-Dependent Methyltransferases.
2006,
Pubmed
Seligson,
Global levels of histone modifications predict prognosis in different cancers.
2009,
Pubmed
Shek,
Fragmentations of protonated arginine, lysine and their methylated derivatives: concomitant losses of carbon monoxide or carbon dioxide and an amine.
2006,
Pubmed
Stupp,
Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.
2015,
Pubmed
Stupp,
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.
2005,
Pubmed
Tentori,
Recent approaches to improve the antitumor efficacy of temozolomide.
2009,
Pubmed
Watanabe,
The cellular level of histone H3 lysine 4 dimethylation correlates with response to adjuvant gemcitabine in Japanese pancreatic cancer patients treated with surgery.
2012,
Pubmed
Wedge,
O6-benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU.
1996,
Pubmed
Wick,
Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082).
2016,
Pubmed
Yin,
Radiotherapy plus concurrent or sequential temozolomide for glioblastoma in the elderly: a meta-analysis.
2013,
Pubmed
Zhang,
Acquired resistance to temozolomide in glioma cell lines: molecular mechanisms and potential translational applications.
2010,
Pubmed
Zhang,
Temozolomide: mechanisms of action, repair and resistance.
2012,
Pubmed
