Iron chelators with topoisomerase-inhibitory activity and their anticancer applications.
CONCLUSIONS
Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents.


BACKGROUND
The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2α). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2α inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome.


RESULTS
While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review.


CONCLUSIONS
Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed.
Laboratory of Biochemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. ashutosh.rao@fda.hhs.gov
V Ashutosh
VA
Rao
D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology; D026942:DNA Topoisomerases / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000009:adverse effects / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D007502:Iron Chelating Agents; D059003:Topoisomerase Inhibitors; D007501:Iron; D026942:DNA Topoisomerases