Cardiac fibrosis in oncologic therapies

Packard, René R. Sevag

doi:10.1016/j.cophys.2022.100575

Cited by 7 publications

(8 citation statements)

References 176 publications

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“…Anthracycline compounds may induce off‐target cardiac injury. Whereas multiple pathobiological mechanisms are at play, and no single pathway can fully recapitulate all aspects of AIC, formation of a Top2β‐Dox‐DNA cleavage complex has been proposed as a key mediator of DNA DSB, transcriptional perturbation, and CM death, complicated by cardiac fibrosis and heart failure 56–58 . Biological processes and protective mechanisms operating within CM to offset anthracycline‐induced injury remain ill‐defined 59 …”

Section: Discussionmentioning

confidence: 99%

“…Whereas mechanisms are at play, and no single pathway can fully recapitulate all aspects of AIC, formation of a Top2β-Dox-DNA cleavage complex has been proposed as a key mediator of DNA DSB, transcriptional perturbation, and CM death, complicated by cardiac fibrosis and heart failure. [56][57][58] Biological processes and protective mechanisms operating within CM to offset anthracycline-induced injury remain ill-defined. 59 Whereas previously associated with an antiproliferative effect in cancer cells, [60][61][62] recent studies in triple negative breast cancer cells indicate Igfbp-3 has an obligatory role in the DNA repair response by activating EGFR and DNA-dependent protein kinase (DNA-PKcs) mediated nonhomologous end-joining (NHEJ), 63 as well as poly (ADP-ribose) polymerase-1 (PARP1) mediated DNA repair.…”

Section: Igfbp-3 Network and Modulesmentioning

confidence: 99%

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Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp‐3 in anthracycline‐induced cardiotoxicity

et al. 2023

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Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracyclineinduced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systemslevel transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human-induced pluripotent stem cell-derived cardiomyocytes. Our findings reveal that Dox induces the nuclear enrichment of

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Section: Discussionmentioning

confidence: 99%

Section: Igfbp-3 Network and Modulesmentioning

confidence: 99%

Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp‐3 in anthracycline‐induced cardiotoxicity

et al. 2023

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“…[18] Furthermore, the role of anti-fibrotic agents should also be explored; anthracyclines lead to cardiac fibrosis which could create a reentry pathway, resulting in arrhythmia. [19] A recent study conducted on mice showed that doxorubicin induced structural and electrical remodeling, leading to increased susceptibility to atrial fibrillation. [20] As such, further studies are warranted to explore the potential benefit of prophylactic anti-fibrotic and anti-arrhythmic drugs in the prevention of arrhythmias among patients receiving anthracyclines.…”

Section: Discussionmentioning

confidence: 99%

Anthracyclines and the risk of arrhythmias: A systematic review and meta-analysis

Dean,

Dahshan,

Motawea

et al. 2023

Medicine

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Background: There have been controversial findings from recent studies regarding anthracyclines use and the subsequent risk of arrhythmias. This study aimed to evaluate the existing evidence of the risk of arrhythmias in patients treated with anthracyclines. Methods: PubMed, Scopus, and Web of Science databases were searched up to April 2022 using keywords such as “anthracycline” and “arrhythmia.” Dichotomous data were presented as relative risk (RR) and confidence interval (CI), while continuous data were presented as mean difference (MD) and CI. Revman software version 5.4 was used for the analysis. Results: Thirteen studies were included with a total of 26891 subjects. Pooled analysis showed that anthracyclines therapy was significantly associated with a higher risk of arrhythmia (RR: 1.58; 95% CI: 1.41–1.76; P < .00001), ST segment and T wave abnormalities (RR: 1.73, 95% CI: 1.18–2.55, P = .005), conduction abnormalities and AV block (RR = 1.86, 95% CI = 1.06–3.25, P = .03), and tachycardia (RR: 1.736, 95% CI: 1.11–2.69, P = .02). Further analyses of the associations between anthracyclines and atrial flutter (RR = 1.30, 95% CI = 0.29–5.89, P = .74), atrial ectopic beats (RR: 1.27, 95% CI: 0.78–2.05, P = .34), and ventricular ectopic beats (RR: 0.93, 95% CI: 0.53–1.65, P = .81) showed no statistically significant results. Higher doses of anthracycline were associated with a higher risk of arrhythmias (RR: 1.49; 95% CI: 1.08–2.05; P = .02) compared to the lower doses (RR: 1.36; 95% CI: 1.00–1.85; P = .05). Newer generations of Anthracycline maintained the arrhythmogenic properties of previous generations, such as Doxorubicin. Conclusion: Anthracyclines therapy was significantly associated with an increased risk of arrhythmias. Accordingly, Patients treated with anthracyclines should be screened for ECG abnormalities and these drugs should be avoided in patients susceptible to arrhythmia. The potential benefit of the administration of prophylactic anti-fibrotic and anti-arrhythmic drugs should also be explored.

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“…viduals [26], the search for additional treatment options becomes imp city encompasses adverse myocardial changes, including fibrosis, tr therapy and radiation [27]. Anthracyclines and radiation are known in development, inducing myocardial injury and inflammation or exert TGF-β [28]. Anti-fibrotic therapies present a potential avenue to cou mental effects on the myocardium during cancer therapy.…”

Section: Inhibiting Tgf-β Directly: Targets In the Signaling Pathwaymentioning

confidence: 99%

Hitting the Target! Challenges and Opportunities for TGF-β Inhibition for the Treatment of Cardiac fibrosis

Vistnes

2024

Pharmaceuticals

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Developing effective anti-fibrotic therapies for heart diseases holds the potential to address unmet needs in several cardiac conditions, including heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, and cardiotoxicity induced by cancer therapy. The inhibition of the primary fibrotic regulator, transforming growth factor (TGF) β, represents an efficient strategy for mitigating fibrosis in preclinical models. However, translating these findings into clinical benefits faces challenges due to potential adverse effects stemming from TGF-β’s physiological actions in inflammation and tissue homeostasis. Various strategies exist for inhibiting TGF-β, each associated with a distinct risk of adverse effects. Targeting TGF-β directly or through its signaling pathway proves efficient in reducing fibrosis. However, direct TGF-β blockade may lead to uncontrolled inflammation, especially following myocardial infarction, while interference with the signaling pathway may compromise structural integrity, resulting in issues like insufficient wound healing or ventricular dilatation. Influencing TGF-β activity through interacting signaling pathways, for instance by inhibitors of the renin–angiotensin–aldosterone-system, is insufficiently potent in reducing fibrosis. Targeting activators of latent TGF-β, including ADAMTS enzymes, thrombospondin, and integrins, emerges as a potentially safer strategy to reduce TGF-β-induced fibrosis but it requires the identification of appropriate targets. Encouragement is drawn from promising agents developed for fibrosis in other organs, fueling hope for similar breakthroughs in treating cardiac fibrosis. Such advances depend on overcoming obstacles for the implementation of anti-fibrotic strategies in patients with heart disease, including fibrosis quantification. In this review, insights garnered from interventional and mechanistic studies, obtained through a non-systemic search spanning preclinical and clinical evidence, are summarized to pinpoint the most promising targets for further exploration and development.

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Cardiac fibrosis in oncologic therapies

Cited by 7 publications

References 176 publications

Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp‐3 in anthracycline‐induced cardiotoxicity

Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp‐3 in anthracycline‐induced cardiotoxicity

Anthracyclines and the risk of arrhythmias: A systematic review and meta-analysis

Hitting the Target! Challenges and Opportunities for TGF-β Inhibition for the Treatment of Cardiac fibrosis

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