Pharmacological senolysis reduces doxorubicin-induced cardiotoxicity and improves cardiac function in mice

Lérida-Viso, Araceli; Estepa-Fernández, Alejandra; Morellá-Aucejo, Ángela; Lozano‐Torres, Beatriz; Alfonso, María; Blandez, Juan F.; Bisbal, Viviana; Sepúlveda, Pilar; García‐Fernández, Alba; Orzáez, Mar; Martínez‐Máñez, Ramón

doi:10.1016/j.phrs.2022.106356

Cited by 40 publications

(28 citation statements)

References 57 publications

(91 reference statements)

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“…Recent studies have found that doxorubicin can trigger senescence of tumor cells while playing antineoplastic roles, and can also induce cellular senescence in normal organs and tissues such as the heart, liver, and skin [25,26,39,40]. As a hazard factor that may gradually erode the normal tissue structure and function, cellular senescence has become a potential target for the treatment of chemotherapy-related injuries.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, fisetin, an antioxidant agent with multiple pharmacological functions, was also identified to have senolytic effects in vivo and in vitro [23,24]. More and more studies have demonstrated that chemotherapy drugs such as doxorubicin and cisplatin can induce cellular senescence in normal tissues like the heart and kidney while playing anti-tumor roles, which may be involved in the pathogenesis of tissue dysfunction [25][26][27]. To date, it remains unclear whether senescent cells increase in the ovary after doxorubicin treatment and whether senolytics can alleviate doxorubicin-induced ovarian damage.…”

Section: Introductionmentioning

confidence: 99%

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Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics

Gao

Tang

et al. 2023

GeroScience

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Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated β-galactosidase (SA-β-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics

Gao

Tang

et al. 2023

GeroScience

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“…This process can be triggered under homeostatic conditions in response to internal stimuli, but may also be induced through pathophysiological means; cardiomyocyte senescence is a hallmark of DOX-induced cardiotoxicity and premature cardiac senescence may be a key aspect of late-onset DOX-toxicity [ 178 ]. Recently, Lerida-Viso and colleagues demonstrated that the hearts of mice repeatedly exposed to DOX over a four week period with a 20 mg/kg cumulative dose, thus mimicking a clinical treatment regimen, significantly overexpressed senescence markers such as p16, p21 and p53 with the simultaneous impairment of cardiac function as measured via echocardiography [ 179 ]. These effects were reversed upon treatment with a senolytic agent [ 179 ].…”

Section: Drug-induced Cardiotoxicity and The Role Of Nrf2mentioning

confidence: 99%

“…Recently, Lerida-Viso and colleagues demonstrated that the hearts of mice repeatedly exposed to DOX over a four week period with a 20 mg/kg cumulative dose, thus mimicking a clinical treatment regimen, significantly overexpressed senescence markers such as p16, p21 and p53 with the simultaneous impairment of cardiac function as measured via echocardiography [ 179 ]. These effects were reversed upon treatment with a senolytic agent [ 179 ].…”

Section: Drug-induced Cardiotoxicity and The Role Of Nrf2mentioning

confidence: 99%

Mitigation of Cardiovascular Disease and Toxicity through NRF2 Signalling

Roberts

Rainbow

Sharma

2023

IJMS

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Cardiovascular toxicity and diseases are phenomena that have a vastly detrimental impact on morbidity and mortality. The pathophysiology driving the development of these conditions is multifactorial but commonly includes the perturbance of reactive oxygen species (ROS) signalling, iron homeostasis and mitochondrial bioenergetics. The transcription factor nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2), a master regulator of cytoprotective responses, drives the expression of genes that provide resistance to oxidative, electrophilic and xenobiotic stresses. Recent research has suggested that stimulation of the NRF2 signalling pathway can alleviate cardiotoxicity and hallmarks of cardiovascular disease progression. However, dysregulation of NRF2 dynamic responses can be severely impacted by ageing processes and off-target toxicity from clinical medicines including anthracycline chemotherapeutics, rendering cells of the cardiovascular system susceptible to toxicity and subsequent tissue dysfunction. This review addresses the current understanding of NRF2 mechanisms under homeostatic and cardiovascular pathophysiological conditions within the context of wider implications for this diverse transcription factor.

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“…Recently, one such senolytic navitoclax (ABT-263), a Bcl-2 family protein inhibitor ( Tse et al, 2008 ), was used to eliminate senescence in a model of DOX-induced cardiac dysfunction ( Lérida-Viso et al, 2022 ). Mice treated with concomitant administration of DOX and navitoclax had fewer senescent cells in their myocardium and an increase in the expression of Sur2a, a marker of cardiac stress tolerance, which decreases in cardiac aging ( Baker et al, 2016 ), and had been reduced by DOX treatment alone.…”

Section: Senescence As a Therapeutic Target For Anthracycline-induced...mentioning

confidence: 99%

Anthracycline-induced cardiotoxicity and senescence

et al. 2022

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Cancer continues to place a heavy burden on healthcare systems around the world. Although cancer survivorship continues to improve, cardiotoxicity leading to cardiomyopathy and heart failure as a consequence of cancer therapy is rising, and yesterday’s cancer survivors are fast becoming today’s heart failure patients. Although the mechanisms driving cardiotoxicity are complex, cellular senescence is gaining attention as a major contributor to chemotherapy-induced cardiotoxicity and, therefore, may also represent a novel therapeutic target to prevent this disease. Cellular senescence is a well-recognized response to clinical doses of chemotherapies, including anthracyclines, and is defined by cell cycle exit, phenotypic alterations which include mitochondrial dysfunction, and the expression of the pro-senescent, pro-fibrotic, and pro-inflammatory senescence-associated phenotype. Senescence has an established involvement in promoting myocardial remodeling during aging, and studies have demonstrated that the elimination of senescence can attenuate the pathophysiology of several cardiovascular diseases. Most recently, pharmacology-mediated elimination of senescence, using a class of drugs termed senolytics, has been demonstrated to prevent myocardial dysfunction in preclinical models of chemotherapy-induced cardiotoxicity. In this review, we will discuss the evidence that anthracycline-induced senescence causes the long-term cardiotoxicity of anticancer chemotherapies, consider how the senescent phenotype may promote myocardial dysfunction, and examine the exciting possibility that targeting senescence may prove a therapeutic strategy to prevent or even reverse chemotherapy-induced cardiac dysfunction.

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Pharmacological senolysis reduces doxorubicin-induced cardiotoxicity and improves cardiac function in mice

Cited by 40 publications

References 57 publications

Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics

Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics

Mitigation of Cardiovascular Disease and Toxicity through NRF2 Signalling

Anthracycline-induced cardiotoxicity and senescence

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