Potential therapeutic advantages of doxorubicin when activated by formaldehyde to function as a dna adduct-forming agent

Suzanne M. Cutts, Ada Rephaeli, Abraham Nudelman, Michal Ugarenko, Don R. Phillips

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Doxorubicin has been in use as a key anticancer drug for forty years, either as a single agent or in combination chemotherapy. It functions primarily by interfering with topoisomerase II activity but in the presence of formaldehyde, it forms adducts with DNA, mainly with the exocyclic amine of guanine at GpC sites and these adducts are more cytotoxic than topoisomerase II induced damage. High levels of adducts form spontaneously from the endogenous level of formaldehyde in tumour cells (1,300 adducts per cell after a 4 hr treatment with doxorubicin), but substantially higher levels form with the addition of exogenous sources of formaldehyde, such as formaldehyde releasing prodrugs. The enhanced cytotoxicity of adducts has been confirmed in mouse models, with adduct-forming conditions resulting in much improved inhibition of tumour growth, as well as cardioprotection. Doxorubicin cardiotoxicity has been attributed to topoisomerase II poisoning, and the cardioprotection is consistent with a mechanism switch from topoisomerase II poisoning to covalent adduct formation. Although the adducts have a half-life of less than one day, a population remains as essentially permanent lesions. The capacity of doxorubicin to form adducts offers a range of potential advantages over the conventional use of doxorubicin (as a topoisomerase II poison), including: enhanced cell kill; tumour-selective activation, hence tumour-selective cell kill; decreased cardiotoxicity; decreased resistance to prolonged doxorubicin treatment. There is therefore enormous potential to improve clinical responses to doxorubicin by using conditions which favour the formation of doxorubicin-DNA adducts.

Original languageEnglish
Pages (from-to)1409-1422
Number of pages14
JournalCurrent Topics in Medicinal Chemistry
Volume15
Issue number14
DOIs
StatePublished - 1 May 2015

Bibliographical note

Publisher Copyright:
© 2015 Bentham Science Publishers

Funding

FundersFunder number
Australian Research Council
Cancer Council Victoria
National Health and Medical Research Council

    Keywords

    • AN-7
    • AN-9
    • Cardiotoxicity
    • Doxorubicin
    • Doxorubicin-DNA adduct
    • Enhanced cytotoxicity
    • Formaldehyde activation
    • Formaldehyde-releasing prodrugs
    • Resistance mechanisms

    Fingerprint

    Dive into the research topics of 'Potential therapeutic advantages of doxorubicin when activated by formaldehyde to function as a dna adduct-forming agent'. Together they form a unique fingerprint.

    Cite this