Voreloxin Is an Anticancer Quinolone Derivative that Intercalates DNA and Poisons Topoisomerase II

Abstract

BackgroundTopoisomerase II is critical for DNA replication, transcription and chromosome segregation and is a well validated target of anti-neoplastic drugs including the anthracyclines and epipodophyllotoxins. However, these drugs are limited by common tumor resistance mechanisms and side-effect profiles. Novel topoisomerase II-targeting agents may benefit patients who prove resistant to currently available topoisomerase II-targeting drugs or encounter unacceptable toxicities. Voreloxin is an anticancer quinolone derivative, a chemical scaffold not used previously for cancer treatment. Voreloxin is completing Phase 2 clinical trials in acute myeloid leukemia and platinum-resistant ovarian cancer. This study defined voreloxin's anticancer mechanism of action as a critical component of rational clinical development informed by translational research.Methods/Principal FindingsBiochemical and cell-based studies established that voreloxin intercalates DNA and poisons topoisomerase II, causing DNA double-strand breaks, G2 arrest, and apoptosis. Voreloxin is differentiated both structurally and mechanistically from other topoisomerase II poisons currently in use as chemotherapeutics. In cell-based studies, voreloxin poisoned topoisomerase II and caused dose-dependent, site-selective DNA fragmentation analogous to that of quinolone antibacterials in prokaryotes; in contrast etoposide, the nonintercalating epipodophyllotoxin topoisomerase II poison, caused extensive DNA fragmentation. Etoposide's activity was highly dependent on topoisomerase II while voreloxin and the intercalating anthracycline topoisomerase II poison, doxorubicin, had comparable dependence on this enzyme for inducing G2 arrest. Mechanistic interrogation with voreloxin analogs revealed that intercalation is required for voreloxin's activity; a nonintercalating analog did not inhibit proliferation or induce G2 arrest, while an analog with enhanced intercalation was 9.5-fold more potent.Conclusions/SignificanceAs a first-in-class anticancer quinolone derivative, voreloxin is a toposiomerase II-targeting agent with a unique mechanistic signature. A detailed understanding of voreloxin's molecular mechanism, in combination with its evolving clinical profile, may advance our understanding of structure-activity relationships to develop safer and more effective topoisomerase II-targeted therapies for the treatment of cancer.

Enhancement of radiosensitivity by the novel anticancer quinolone derivative vosaroxin in preclinical glioblastoma models

“…Vosaroxin is a naphthyridine analog (Figure 1), structurally related to quinolone antibacterials, that exerts its anticancer activity exclusively by DNA intercalation and inhibition of topoisomerase II, leading to site-selective DNA double-strand breaks and apoptosis [26][27][28]. Vosaroxin is not a substrate for P-glycoprotein drug pumps, and can induce apoptosis independent of p53, thereby avoiding two common mechanisms of drug resistance [29].…”

Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML?

“…Interest in the use of quinolone analogs as cytotoxics began after initial research showed that they have the potential to interact with mammalian topoisomerases [17][18][19][20]. Vosaroxin is a first-in-class cytotoxic quinolone derivative that intercalates in DNA and inhibits topoisomerase II (topo II) [21][22][23][24]. It has been shown to be a replication-dependent DNA damaging agent, causing irreversible G2 arrest and rapid apoptosis.…”

“…Vosaroxin has several advantages over these agents: more favorable pharmacologic properties, the potential to overcome resistance mechanisms and a stable quinolone core. Experimental data suggest that vosaroxin does not produce significant levels of reactive oxygen species (ROS) compared with doxorubicin [21], with extrapolated decreased risk of ROS-induced cardiotoxicity. These properties may hold the key to achieve meaningful outcomes when treating older patients and patients with relapsed and refractory chemo-resistant disease and will be reviewed in depth in this article.…”

“…Vosaroxin is a naphthyridine-derived small molecule that exists as a 'zwitterion'-containing carboxylic acid and amine functional groups [47]. It has no antibacterial activity, but shares structural similarity with quinolone antimicrobials (Figure 1) [21].…”

“…Similar to the anthracyclines, vosaroxin intercalates in DNA causing site-selective DSB at GC/GG-rich sequences [21]. The DNA DSB that result from exposure to vosaroxin are preferentially induced in actively replicating cells [22].…”