M2, a novel anthracenedione, elicits a potent DNA damage response that can be subverted through checkpoint kinase inhibition to generate mitotic catastrophe
- Author(s)
- Evison, BJ; Pastuovic, M; Bilardi, RA; Forrest, RA; Pumuye, PP; Sleebs, BE; Watson, KG; Phillips, DR; Cutts, SM;
- Details
- Publication Year 2011-12-01,Volume 82,Issue #11,Page 1604-1618
- Journal Title
- BIOCHEMICAL PHARMACOLOGY
- Publication Type
- Journal Article
- Abstract
- Pixantrone is a promising anti-cancer aza-anthracenedione that has prompted the development of new anthracenediones incorporating symmetrical side-chains of increasing length varying from two to five methylene units in each pair of drug side-chains. A striking relationship has emerged in which anthracenedione-induced growth inhibition and apoptosis was inversely associated with side-chain length, a relationship that was attributable to a differential ability to stabilise the topoisomerase II (TOP2) cleavage complex. Processing of the complex to a DNA double strand break (DSB) flanked by gamma H2AX in nuclear foci is likely to occur, as the generation of the primary lesion was antecedent to gamma H2AX induction. M2, bearing the shortest pair of side-chains, induced TOP2-mediated DSBs efficiently and activated cell cycle checkpoints via Chk1 and Chk2 phosphorylation, implicating the involvement of ATM and AIR, and induced a protracted S phase and subsequent G2/M arrest. The inactive analogue M5, containing the longest pair of side-chains, only weakly stimulated any of these responses, suggesting that efficient stabilisation of the TOP2 cleavage complex was crucial for eliciting a strong DNA damage response (DDR). An M2 induced DDR in p53-defective MDA-MB-231 cells was abrogated by UCN-01, a ubiquitous inhibitor of kinases including Chk1, in a response associated with substantial mitotic catastrophe and strong synergy. The rational selection of checkpoint kinase inhibitors may significantly enhance the therapeutic benefit of anthracenediones that efficiently stabilise the TOP2 cleavage complex. (C) 2011 Elsevier Inc. All rights reserved.
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- DOUBLE-STRAND BREAKS; TOPOISOMERASE-II; HISTONE H2AX; TUMOR-CELLS; ADDUCT FORMATION; NUCLEIC-ACIDS; S-PHASE; MITOXANTRONE; CANCER; DRUG
- Publisher's Version
- https://doi.org/10.1016/j.bcp.2011.08.013
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- Refer to copyright notice on published article.
Creation Date: 2011-12-01 12:00:00