TY - JOUR
T1 - Uncoupling DNA damage from chromatin damage to detoxify doxorubicin
AU - Qiao, Xiaohang
AU - van der Zanden, Sabina Y.
AU - Wander, Dennis P.A.
AU - Borràs, Daniel M.
AU - Song, Ji Ying
AU - Li, Xiaoyang
AU - van Duikeren, Suzanne
AU - van Gils, Noortje
AU - Rutten, Arjo
AU - van Herwaarden, Tessa
AU - van Tellingen, Olaf
AU - Giacomelli, Elisa
AU - Bellin, Milena
AU - Orlova, Valeria
AU - Tertoolen, Leon G.J.
AU - Gerhardt, Sophie
AU - Akkermans, Jimmy J.
AU - Bakker, Jeroen M.
AU - Zuur, Charlotte L.
AU - Pang, Baoxu
AU - Smits, Anke M.
AU - Mummery, Christine L.
AU - Smit, Linda
AU - Arens, Ramon
AU - Li, Junmin
AU - Overkleeft, Hermen S.
AU - Neefjes, Jacques
N1 - Funding Information: ACKNOWLEDGMENTS. We thank the animal facility at the NKI and the LUMC for support, Jos Jonkers for Trp53 heterozygous mice, Ilana Berlin for critical reading of the manuscript, Berend van Meer for help with contraction data analysis, Cun Wang and Wenxin Qin for helpful discussion on AML patient data, and Lennert Janssen for movie editing. This work was supported by European Research Council (ERC) advanced grant and Koningin Wilhelmina Fonds (KWF) grants to J.N. and to C.L.M., RIKI foundation (C.L.Z.), the Institute for Chemical Immunology, and an Nederlandse Organ-isatie voor Wetenschappelijk Onderzoek (NWO) Gravitation project funded by the Ministry of Education, Culture and Science of the Netherlands (H.S.O. and J.N.). Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/30
Y1 - 2020/6/30
N2 - 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 mechanism of 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.
AB - 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 mechanism of 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.
KW - Cardiotoxicity
KW - Chromatin Damage
KW - DNA damage
KW - Therapy-Related Tumors
KW - doxorubicin
UR - http://www.scopus.com/inward/record.url?scp=85087465598&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1922072117
DO - https://doi.org/10.1073/pnas.1922072117
M3 - Article
C2 - 32554494
SN - 0027-8424
VL - 117
SP - 15182
EP - 15192
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
IS - 26
ER -