Tieli Wang1, Amanda J Pickard2, James M Gallo3. 1. Department of Chemistry and Biochemistry, California State University Dominguez Hills, Carson, CA, U.S.A. twang@csudh.edu james.gallo@mssm.edu. 2. Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, U.S.A. 3. Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, U.S.A. twang@csudh.edu james.gallo@mssm.edu.
Abstract
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. Copyright
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. Copyright
Authors: Roger Stupp; Sophie Taillibert; Andrew A Kanner; Santosh Kesari; David M Steinberg; Steven A Toms; Lynne P Taylor; Frank Lieberman; Antonio Silvani; Karen L Fink; Gene H Barnett; Jay-Jiguang Zhu; John W Henson; Herbert H Engelhard; Thomas C Chen; David D Tran; Jan Sroubek; Nam D Tran; Andreas F Hottinger; Joseph Landolfi; Rajiv Desai; Manuela Caroli; Yvonne Kew; Jerome Honnorat; Ahmed Idbaih; Eilon D Kirson; Uri Weinberg; Yoram Palti; Monika E Hegi; Zvi Ram Journal: JAMA Date: 2015-12-15 Impact factor: 56.272
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