Action of SN 28049, a new DNA binding topoisomerase II-directed antitumour drug: comparison with doxorubicin and etoposide

Abstract

The action of SN 28049 in NZM3 cells is typical of a topoisomerase II poison, but the low topoisomerase IIα activity of HCT116 cells allowed the detection of a second antiproliferative action of SN 28049 in which cells undergo post-mitotic cycle arrest and induction of p53.

Trovafloxacin Enhances Lipopolysaccharide-Stimulated Production of Tumor Necrosis Factor-αby Macrophages: Role of the DNA Damage Response

“…Human TopIIa was selected for analysis because it is the eukaryotic homolog to prokaryotic DNA gyrase and topoisomerase IV (Bates et al, 2011;Drummond et al, 2011). TVX binding to eukaryotic TopIIa occurred at two binding sites (Fig.…”

“…Poisoning of topoisomerase activity in cells leads to several outcomes, one of which is the formation of double-stranded lesions in DNA (Ryan et al, 1991;Drummond et al, 2011). Phosphorylated histone 2A.X (pH2A.X) is a sensitive marker of DNA lesions.…”

“…Taken together, these results raised the possibility that the IDILI liability associated with TVX might be attributed to off-target poisoning of eukaryotic topoisomerase. Topoisomerase inhibition in cells can lead to double-strand DNA breaks generated from topoisomerase-DNA covalent complexes (Liu et al, 1983;Ryan et al, 1991;Li et al, 2010;Drummond et al, 2011). pH2A.X was chosen as a sensitive marker of double-strand DNA breaks.…”

“…Interestingly, in addition to their ability to inhibit prokaryotic topoisomerases, the fluoroquinolones TVX, CPX, and MOX have weak inhibitory activity against eukaryotic topoisomerase II-a (TopIIa) (Barrett et al, 1989;Albertini et al, 1995;Herbold et al, 2001;Reuveni et al, 2008). It is well recognized that inhibiting ("poisoning") topoisomerases can lead to DNA damage (Ryan et al, 1991;Drummond et al, 2011). DNA damage prompts intracellular signaling involving activation of kinases that might enhance TNF expression.…”

In vivo and in vitro assessment of the action of SN 28049, a benzonaphthyridine derivative targeting topoisomerase II, on the murine Colon 38 carcinoma

“…SN 28049 (Fig. 1), the most active of these derivatives, is a topoisomerase II poison [7,8] and its high activity against the Colon 38 tumour contrasts sharply with that of another topoisomerase II poison etoposide [4]. Here, we have addressed the question of why Colon 38 tumours respond so differently to two drugs that have the same target of action.…”