title: The cardio-protecting agent and topoisomerase II catalytic inhibitor sobuzoxane enhances doxorubicin-DNA adduct mediated cytotoxicity.
abstract: OBJECTIVE
  The importance of understanding the mechanism of action of anticancer agents is sometimes overlooked in the pursuit of new and therapeutically advantageous compounds. Doxorubicin has long been identified as an inhibitor of the DNA-decatenating enzyme topoisomerase II, this being believed to be the major mechanism of action of this drug. However, the complex nature of cytotoxicity induced by doxorubicin suggests that more than one mechanism of action is responsible for cell kill. Investigation into various other cellular effects has shown that doxorubicin can, in the presence of formaldehyde, form doxorubicin-DNA adducts, resulting in enhanced cell death.
  
  
  METHODS
  We have used six catalytic inhibitors of topoisomerase II (aclarubicin, merbarone, suramin, staurosporine, maleimide and sobuzoxane) to investigate the role of topoisomerase II mediated cell effects in doxorubicin-DNA adduct inducing treatments. Adduct levels were determined by scintillation counting of [14C]doxorubicin-DNA lesions and DNA damage responses by Comet analysis and flow cytometry (apoptosis).
  
  
  RESULTS
  Here we show that sobuzoxane inhibits topoisomerase II but in the presence of doxorubicin also enhances the production of doxorubicin-DNA adducts resulting in an enhanced cytotoxic response. We show that the formation of doxorubicin-DNA adducts is mediated by formaldehyde released from sobuzoxane when it is metabolised.
  
  
  CONCLUSIONS
  Sobuzoxane has also been shown to decrease the normally dose limiting cardiotoxicity commonly exhibited with clinical use of doxorubicin. The potential combination of doxorubicin and sobuzoxane in cancer chemotherapy has two advantages. First, the mechanism of doxorubicin toxicity is shifted away from topoisomerase II inhibition and towards drug-DNA adduct formation which may allow for a lower drug dose to be used and circumvent some drug resistance problems. Second, the addition of a cardioprotecting agent will counteract the commonly dose limiting side effect of cardiac damage resulting from doxorubicin treatment. The importance of the potentiation of cell kill of doxorubicin and sobuzoxane provides a rationalisation of a mechanistic-based combination of anticancer drugs for an improved clinical outcome.
authors.affiliation: Department of Biochemistry, La Trobe University, Bundoora, VIC 3086, Australia.
authors.forename: Lonnie P
authors.initials: LP
authors.lastname: Swift
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cutts
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: Inessa
authors.initials: I
authors.lastname: Levovich
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
authors.forename: Don R
authors.initials: DR
authors.lastname: Phillips
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020552:Comet Assay; D018736:DNA Adducts / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D005557:Formaldehyde / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012588:Scintillation Counting; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C031902:doxorubicin-DNA; D005557:Formaldehyde; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C057773:sobuzoxane