Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

Qiao, Xiaohang; Zanden, Sabina Y. van der; Wander, Dennis P A; Borràs, Daniel; Song, Ji‐Ying; Li, Xiaoyang; Duikeren, Suzanne van; Gils, Noortje van; Rutten, Arjo P.; Herwaarden, Tessa van; Tellingen, Olaf van; Giacomelli, Elisa; Bellin, Milena; Orlova, Valeria V.; Tertoolen, Leon G.J.; Gerhardt, Sophie; Akkermans, Jimmy J.L.L.; Bakker, Jeroen; Zuur, Charlotte L.; Pang, Baoxu; Smits, Anke M.; Mummery, Christine L.; Smit, Linda; Arens, Ramon; Li, Junmin; Overkleeft, Hermen S.; Neefjes, Jacques

doi:10.1073/pnas.1922072117

Cited by 104 publications

(166 citation statements)

References 68 publications

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“…We believe that this was at least in part due to mechanism we have proposed. However, DOX, with or without ROS, can cause damage to numerous, if not all, organelles in a cell [64][65][66][67][68][69]. Our study focused on the mitochondria with a potential mechanism that had been observed under specific circumstances in other studies.…”

Section: Plos Onementioning

confidence: 99%

Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts

Mancilla

Davis²,

Aune

2020

PLoS ONE

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Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.

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Section: Plos Onementioning

confidence: 99%

Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts

Mancilla

Davis²,

Aune

2020

PLoS ONE

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“… 12 , 13 However, aclarubicin, which has a higher redox potential than doxorubicin, 14 displays fewer cardiotoxic side effects, and recent findings in our labs suggested that this difference in cardiotoxicity relates to significant differences in the mode of action of these two compounds. 15 Doxorubicin causes chromatin damage by inducing histone eviction, as well as the formation of DNA double-strand breaks by poisoning topoisomerase IIα (TopoIIα). 16 , 17 Aclarubicin is capable of evicting histones as well, but targets TopoIIα without inducing DNA double-strand breaks.…”

Section: Introductionmentioning

confidence: 99%

“…Aclarubicin and N , N -dimethyldoxorubicin ( 3 ) both lack DNA damage activity but are able to induce histone eviction, and can thus be used as effective anticancer drugs without cardiotoxicity. 15 The structural basis causing this difference in biological activities, however, is still lacking. Therefore, better insight into the structure–function relationship of these molecules is needed.…”

Section: Introductionmentioning

confidence: 99%

“…26 In spite of this, the chemical space between doxorubicin and aclarubicin has not been fully explored. Although some doxorubicin/aclarubicin hybrids have been prepared (including compounds 2 , 27 3 , 15 , 28 4 , 29 8 , 30 10 , 31 and 11 ( 32 )), the reported methods of synthesis are fragmented and the complete set, as shown in Figure 1 , has not been evaluated in the context of the different modes of action described above. We therefore set out to generate a comprehensive set of doxorubicin/aclarubicin hybrid structures, systematically varying the structural elements in which the two anthracyclines differ.…”

Section: Introductionmentioning

confidence: 99%

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Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents

et al. 2020

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Anthracycline anticancer drugs doxorubicin and aclarubicin have been used in the clinic for several decades to treat various cancers. Although closely related structures, their molecular mode of action diverges, which is reflected in their biological activity profile. For a better understanding of the structure–function relationship of these drugs, we synthesized ten doxorubicin/aclarubicin hybrids varying in three distinct features: aglycon, glycan, and amine substitution pattern. We continued to evaluate their capacity to induce DNA breaks, histone eviction, and relocated topoisomerase IIα in living cells. Furthermore, we assessed their cytotoxicity in various human tumor cell lines. Our findings underscore that histone eviction alone, rather than DNA breaks, contributes strongly to the overall cytotoxicity of anthracyclines, and structures containing N , N -dimethylamine at the reducing sugar prove that are more cytotoxic than their nonmethylated counterparts. This structural information will support further development of novel anthracycline variants with improved anticancer activity.

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“…In fact, aclarubicin is not available for clinical testing beyond Japan and China, where it is mainly used for hematological tumors [22]. A potential advantage of aclarubicin is the reduced cardiotoxicity and limited toxicity on reproductive organs, common side effects of other chemotherapies including doxo-and daunorubicin, mitoxantrone and 5-FU [23,24]. Furthermore, as cardiotoxicity is treatment limiting, aclarubicin may be used in combination with other drugs or with more extensive treatment regimens compared to other chemotherapeutics [25].…”

Section: Introductionmentioning

confidence: 99%

The Identification of the Anthracycline Aclarubicin as an Effective Cytotoxic Agent for Pancreatic Cancer

Brouwer¹,

Zanden²,

Eendenburg³

et al. 2020

Preprint

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, mainly due to its delayed diagnosis and lack of effective therapeutic options. Therefore, it is imperative to find novel treatment options for PDAC. Here, we tested a series of conventional chemotherapeutics together with anthracycline compounds as single agents or in combination, determining their effectivity against established commercial and patient-derived, low passage PDAC cell lines.MethodsProliferation and colony formation assays were performed to determine the anti-cancer activity of anthracyclines; aclarubicin and doxorubicin, on commercial and patient-derived, low passage PDAC cell lines. In addition, the effect of standard of care drugs gemcitabine and individual components of FOLFIRINOX were also investigated. The assays involved short-term exposure to the drugs in order to mimic pharmacokinetics in a patient.ResultsAclarubicin showed superior anti-tumor activity compared to other anthracyclines and standard of care drugs (gemcitabine and individual components of FOLFIRINOX) in a patient-derived, low passage PDAC cell line. Importantly, the combination of gemcitabine and aclarubicin showed a synergistic effect at a dose range where the single agents by themselves were ineffective. Subsequent testing in commercial cell lines showed similar cytotoxic effects of aclarubicin in two out of three cell lines. Gemcitabine and doxorubicin had variable responses between the cell lines, but their effect never exceeded that of aclarubicin.ConclusionsAclarubicin is cytotoxic for commercial and patient-derived low-passage PDAC cell lines, at doses lower than peak serum concentrations for patient treatment. Our findings support a (re-)consideration of aclarubicin as a backbone of new combination regimens for pancreatic cancer patients.

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Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

Cited by 104 publications

References 68 publications

Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts

Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts

Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents

The Identification of the Anthracycline Aclarubicin as an Effective Cytotoxic Agent for Pancreatic Cancer

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