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

Autor: Wenjin Yang, Jo Ann W. Byl, Neil Osheroff, Andrew Conroy, Rachael E. Hawtin, Judith A. Fox, David E. Stockett, Robert S. McDowell, Nguyen Tan, Michelle R. Arkin
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Non-Clinical Medicine
lcsh:Medicine
Apoptosis
Pharmacology
Quinolones
Vosaroxin
Biochemistry
chemistry.chemical_compound
0302 clinical medicine
Drug Delivery Systems
Oncology/Hematological Malignancies
lcsh:Science
Etoposide
0303 health sciences
Multidisciplinary
biology
Hematology/Acute Myeloid Leukemia
Quinolone
Intercalating Agents
3. Good health
Chemical Biology/Small Molecule Chemistry
Oncology
030220 oncology & carcinogenesis
Oncology/Breast Cancer
DNA fragmentation
Biochemistry/Drug Discovery
medicine.drug
Research Article
G2 Phase
DNA damage
medicine.drug_class
Oncology/Oncology Agents
Antineoplastic Agents
DNA Fragmentation
03 medical and health sciences
Epipodophyllotoxin
Cell Line
Tumor
medicine
Humans
Doxorubicin
Naphthyridines
Molecular Biology
030304 developmental biology
Molecular Biology/DNA Repair
Topoisomerase
lcsh:R
Biochemistry/Chemical Biology of the Cell
DNA
Cell Biology
Thiazoles
DNA Topoisomerases
Type II
chemistry
biology.protein
lcsh:Q
DNA Damage
Pharmacology/Drug Development
Zdroj: PLoS ONE, Vol 5, Iss 4, p e10186 (2010)
PLoS ONE
ISSN: 1932-6203
Popis: Background 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. Methods/Principal Findings 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. Conclusions/Significance 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.
Databáze: OpenAIRE
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