Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II

• Published in: PloS one Vol. 5; no. 4; p. e10186
• Main Authors: Hawtin, Rachael E, Stockett, David E, Byl, Jo Ann W, McDowell, Robert S, Nguyen, Tan, Arkin, Michelle R, Conroy, Andrew, Yang, Wenjin, Osheroff, Neil, Fox, Judith A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.04.2010; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Analogs; Anthracycline; Anthracyclines; Antineoplastic Agents - pharmacology; Apoptosis; Biochemistry; Biochemistry/Chemical Biology of the Cell; Biochemistry/Drug Discovery; Cancer; Cancer research; Cancer therapies; Cancer treatment; Cell Biology; Cell cycle; Cell Line, Tumor; Chemical Biology/Small Molecule Chemistry; Clinical trials; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA biosynthesis; DNA Damage; DNA fragmentation; DNA Fragmentation - drug effects; DNA replication; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerases, Type II - drug effects; Doxorubicin; Drug delivery; Drug Delivery Systems; Drug dosages; Drug resistance; Drug therapy; Drugs; Enzymes; Etoposide; Etoposide - pharmacology; Fragmentation; G2 Phase; Genetic aspects; Genetic research; Hematology/Acute Myeloid Leukemia; Humans; Intercalating Agents; Intercalation; Interrogation; Leukemia; Medical research; Medicine; Molecular Biology; Molecular Biology/DNA Repair; Myeloid leukemia; Naphthyridines - pharmacology; Naphthyridines - therapeutic use; Non-Clinical Medicine; Oncology; Oncology/Breast Cancer; Oncology/Hematological Malignancies; Oncology/Oncology Agents; Ovarian cancer; Ovarian carcinoma; Pharmaceuticals; Pharmacology/Drug Development; Platinum; Poisoning; Poisons; Prokaryotes; Quinolones - chemistry; Quinolones - pharmacology; Saccharomyces cerevisiae; Side effects; Structure-activity relationships; Thiazoles - pharmacology; Thiazoles - therapeutic use; Toxicity; Transcription; Transcription (Genetics); Yeast; Palo Alto California; San Francisco California; United States > US; Tennessee; South San Francisco California; California; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010186

Topoisomerase 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. Biochemical 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. As 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.