Brad Sleebs - M2, a novel anthracenedione, elicits a potent DNA damage response that can be subverted through checkpoint kinase inhibition to generate mitotic catastrophe.

Document created by Brad Sleebs on Aug 22, 2014
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  Publication Details (including relevant citation   information):

  Biochemical   Pharmacology (2011),   82(11),   1604-1618.


  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 γH2AX in   nuclear foci is likely to occur, as the generation of the primary   lesion was antecedent to γH2AX 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 ATR,   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.

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