Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiot...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2020-06, Vol.117 (26), p.15182-15192
Main Authors: Qiao, Xiaohang, van der Zanden, Sabina Y., Wander, Dennis P. A., Borràs, Daniel M., Song, Ji-Ying, Li, Xiaoyang, van Duikeren, Suzanne, van Gils, Noortje, Rutten, Arjo, van Herwaarden, Tessa, van Tellingen, Olaf, Giacomelli, Elisa, Bellin, Milena, Orlova, Valeria, Tertoolen, Leon G. J., Gerhardt, Sophie, Akkermans, Jimmy J., Bakker, Jeroen M., Zuur, Charlotte L., Pang, Baoxu, Smits, Anke M., Mummery, Christine L., Smith, Linda, Arens, Ramon, Li, Junmin, Overkleeft, Hermen S., Neefjes, Jacques
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Anthracycline
Anticancer properties
Biological Sciences
Cancer
Cardiotoxicity
Chromatin
Cytotoxicity
Damage
Daunorubicin
Deoxyribonucleic acid
DNA
DNA damage
DNA topoisomerase (ATP-hydrolysing)
Doxorubicin
Epirubicin
Etoposide
Genomes
Infertility
Leukemia
Myeloid leukemia
Patients
Poisons
Quality of life
Side effects
Therapy
Tumors
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Summary:The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanismof anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1922072117