Doxorubicin cardiotoxicity and target cells: a broader perspective

Angelis, Antonella De; Urbanek, Konrad; Cappetta, Donato; Piegari, Elena; Ciuffreda, Loreta Pia; Rivellino, Alessia; Russo, Rosa; Esposito, Grazia; Rossi, Francesco; Berrino, Liberato

doi:10.1186/s40959-016-0012-4

Cited by 65 publications

(44 citation statements)

References 105 publications

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“…Therefore, to understand and mitigate DOX induced chronic DCM, several excellent reviews have focused on the effect of DOXderegulated oxidative metabolism [11,12], DOX-induced autophagy [13], or on the broader clinical scope of DOX-induced DCM [14]. We here focus on the role of apoptosis to discuss potential molecular underpinnings of a chronic DCM phenotype, paying specific attention on apoptosis alteration after cardiomyocyte differentiation and DOX exposure.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

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Section: Introductionmentioning

confidence: 99%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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“…This may effect proteins, lipids and other pathways not represented in this model, including calcium dysregulation [31] and mitochondrial permeability transition [32]. It has also been proposed that DOX removes proginator cells that may contribute to a heart failure phenotype [33]. These may be contributing factors, however, the observed increase in ROS production and decrease in mtDNA content are consistent with the mitochondria playing a prominent role in DOX cardiotoxicity.…”

Section: Discussionmentioning

confidence: 83%

A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity

Oliveira

Niederer

2016

PLoS Comput Biol

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The clinical use of the anthracycline doxorubicin is limited by its cardiotoxicity which is associated with mitochondrial dysfunction. Redox cycling, mitochondrial DNA damage and electron transport chain inhibition have been identified as potential mechanisms of toxicity. However, the relative roles of each of these proposed mechanisms are still not fully understood. The purpose of this study is to identify which of these pathways independently or in combination are responsible for doxorubicin toxicity. A state of the art mathematical model of the mitochondria including the citric acid cycle, electron transport chain and ROS production and scavenging systems was extended by incorporating a novel representation for mitochondrial DNA damage and repair. In silico experiments were performed to quantify the contributions of each of the toxicity mechanisms to mitochondrial dysfunction during the acute and chronic stages of toxicity. Simulations predict that redox cycling has a minor role in doxorubicin cardiotoxicity. Electron transport chain inhibition is the main pathway for acute toxicity for supratherapeutic doses, being lethal at mitochondrial concentrations higher than 200μM. Direct mitochondrial DNA damage is the principal pathway of chronic cardiotoxicity for therapeutic doses, leading to a progressive and irreversible long term mitochondrial dysfunction.

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“…Thus, we subjected cancer 3 cells to 48 hours of microgravity and used standard migration assays to compare the migratory abilities of chemotherapy treated and untreated cancer cells, in order to assess whether microgravity alters our hitherto reported (14) inadvertent pro-metastatic effect of the anti-cancer drugs: daunorubicin (Dauno) and doxorubicin (Dox). Both Dox and Dauno are commonly used in the clinic against several cancers such as breast, lung and ovarian cancers, malignant melanomas and leukemia (18,19). Interestingly, we find that post-microgravity chemotherapy using Dauno leads to increased chemotactic migration (p < 0.01) compared to normal gravity (1g) on earth in which there was reduced migration with Dauno.…”

Section: Introductionmentioning

confidence: 73%

Microgravity modulates effects of chemotherapeutic drugs on cancer cell migration

Prasanth

Suresh

Prathivadhi-Bhayankaram

et al. 2019

Preprint

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Microgravity or the condition of apparent weightlessness causes bone, muscular and immune system dysfunctions in astronauts following spaceflights. These organ and system-level dysfunctions correlate with changes induced at the single cell level both by simulated microgravity on earth as well as microgravity conditions in outer space (as in the international space station). Reported changes in single bone cells, muscle cells and white blood cells include structural/morphological abnormalities, changes in gene expression, protein expression, metabolic pathways and signaling pathways, suggesting that cells mount some response or adjustment to microgravity. However, the implications of such adjustments on many cellular functions and responses are not clear largely because the primary mechanism of gravity sensing in animal cells is unknown. Here we used a rotary cell culture system developed by NASA, to subject leukemic and erythroleukemic cancer cells to microgravity for 48 hours and then quantified their innate immune-response to common anti-cancer drugs using biophysical parameters and our recently developed quantum-dots-based fluorescence spectroscopy. We found that leukemic cancer cells treated with daunorubicin show increased chemotactic migration (p < 0.01) following simulated microgravity (µg) compared to normal gravity on earth (1g). However, cells treated with doxorubicin showed enhanced migration both in 1g and following µg. Our results show that microgravity modulates cancer cell response to chemotherapy in a drug-dependent manner. These results suggest using simulated microgravity as an immunomodulatory tool for the development of new immunotherapies for both space and terrestrial medicine.

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Doxorubicin cardiotoxicity and target cells: a broader perspective

Cited by 65 publications

References 105 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity

Microgravity modulates effects of chemotherapeutic drugs on cancer cell migration

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