Cancer patients treated with doxorubicin are at risk of congestive heart failure due to doxorubicin-mediated cardiotoxicity via topoisomerase IIβ poisoning. Acute cardiac muscle damage occurs in response to the very first dose of doxorubicin, however, cardioprotection has been reported after co-treatment of doxorubicin with acyloxyalkyl ester prodrugs. The aim of this study was to examine the role played by various forms of acute cardiac damage mediated by doxorubicin and determine a mechanism for the cardioprotective effect of formaldehyde-releasing prodrug AN-9 (pivaloyloxymethyl butyrate). Doxorubicin-induced cardiac damage in BALB/c mice bearing mammary tumours was established with a single dose of doxorubicin (4 or 16 mg/kg) administered alone or in combination with AN-9 (100 mg/kg). AN-9 protected the heart from doxorubicin-induced myocardial apoptosis and also significantly reduced dsDNA breaks, independent from the level of doxorubicin biodistribution to the heart. Covalent incorporation of [14C]doxorubicin into DNA showed that the combination treatment yielded significantly higher levels of formaldehyde-mediated doxorubicin-DNA adducts compared to doxorubicin alone, yet this form of damage was associated with cardioprotection from apoptosis. The cardiac transcriptomic analysis indicates that the combination treatment initiates inflammatory response signalling pathways. Doxorubicin and AN-9 combination treatments were cardioprotective, yet preserved doxorubicin-mediated anti-tumour proliferation and apoptosis in mammary tumours. This was associated with a switch in doxorubicin action from cardiac topoisomerase IIβ poisoning to covalent-DNA adduct formation. Co-administration of doxorubicin and formaldehyde-releasing prodrugs, such as AN-9, may be a promising cardioprotective therapy while maintaining doxorubicin activity in primary mammary tumours.
Bibliographical noteFunding Information:
This work was supported by the National Breast Cancer Foundation (SMC & BSP, IIRS-18-026), National Health and Medical Research Council (SMC & SP, GNT1049818), Cancer Council Victoria (BSP, 1127757), The CASS Foundation (SMC, 6253), fellowship support from the Victorian Cancer Agency (BSP, MCRF16022) and Israel Cancer Research Fund USA (AR, 0601564411).
This work was supported by the National Breast Cancer Foundation (SMC & BSP, IIRS-18-026), National Health and Medical Research Council (SMC & SP, GNT1049818), Cancer Council Victoria (BSP, 1127757), The CASS Foundation (SMC, 6253), fellowship support from the Victorian Cancer Agency (BSP, MCRF16022) and Israel Cancer Research Fund USA (AR, 0601564411). The authors acknowledge the contribution from La Trobe University Genomics Platform, La Trobe University Bioimaging Platform, La Trobe Animal Research and Teaching Facility, La Trobe Histology Suite, Emeritus Prof Don R. Phillips, Prof Robin Anderson and Manal Farg.
© 2021 Elsevier Inc.
- Anthracycline chemotherapy
- Doxorubicin-DNA adduct
- Doxorubicin-induced cardiotoxicity
- Formaldehyde-releasing prodrug
- Triple negative breast cancer