Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks

Abstract

AbstrAct:Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality.

Detection of DNA double‐strand breaks by pulsed‐field gel electrophoresis

“…2B-F). These results were consistent with those of previous studies (Vock et al 1998;Arnaudeau et al 2001;Hanada et al 2006;Hawtin et al 2010).…”

“…In particular, the process of DNA replication can induce physiological DSB formation (Hanada et al 2006(Hanada et al , 2007Hawtin et al 2010;Ashour et al 2015). To date, two distinct mechanisms have been proposed (Hanada et al 2006(Hanada et al , 2007Hawtin et al 2010;Ashour et al 2015). One mechanism involves the progression of DNA replication forks over SSB sites on the template strand, resulting in DSB formation (Ashour et al 2015).…”

Matricellular protein CCN1 mediates doxorubicin-induced cardiomyopathy in mice

“…The risks of latent tumorigenesis resulting from disrupting CCN1/α 6 β 1 signaling long term need to be further evaluated. Nevertheless, because replicating cells are more sensitive to DOX [2], cotreatment of DOX likely will compensate the loss of the antineoplastic activities from disrupting CCN1/α 6 β 1 signaling in hepatocytes.…”

“…The antitumor activity of DOX is attributable to its ability to intercalate DNA helix and inhibit topoisomerase II, causing DNA double strand breaks, G2 arrest and apoptosis in replicating cells [2]. Despite its effectiveness against cancer, the clinical use of DOX is critically limited by its cumulative cardiotoxicity [3].…”

Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia

“…Vosaroxin is a first-in-class anticancer quinolone derivative with a unique mechanism of action and drug-resistance profile that are distinct from those of other anticancer agents [80,81]. Vosaroxin induces replication-dependent DNA damage by intercalating into DNA and blocking topoisomerase II-mediated religation, ultimately leading to apoptosis [76].…”