Temozolomide and carmustine cause large-scale heterochromatin reorganization in glioma cells
- Dialectica s.r.l V.le Pasteur 10, 20014 Nerviano, Milan (Italy)
- Neurosurgery, Department of Surgery, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, 27100 Pavia (Italy)
- Centre for Stem Cells Research and Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan (Italy)
Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957-1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359-367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1{alpha} bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.
- OSTI ID:
- 21255867
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 379, Issue 2; Other Information: DOI: 10.1016/j.bbrc.2008.12.091; PII: S0006-291X(08)02487-X; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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