Clinical and preclinical evidence of sex-related differences in anthracycline-induced cardiotoxicity

Meiners, Becky; Shenoy, Chetan; Zordoky, Beshay N.

doi:10.1186/s13293-018-0198-2

Cited by 56 publications

(46 citation statements)

References 86 publications

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“…Indeed, nutraceuticals with anti-inflammatory properties such as lycopene, curcumin, and resveratrol have been shown to reduce the toxicity and improve the efficacy of chemotherapeutic agents [14,27]. We and others have reported significant sex-related differences in acute and chronic DOX-induced cardiotoxicity and nephrotoxicity in experimental animals [11,[28][29][30][31][32]. Sexual dimorphism of acute DOX-induced cardiotoxicity is associated with higher expression of inflammatory genes in the heart of male than female mice [11].…”

Section: Discussionmentioning

confidence: 83%

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

Grant

Abdelgawad

Lewis

et al. 2020

IJMS

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Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of malignancies. In addition to its multi-organ toxicity, DOX treatment has been shown to induce systemic inflammation in patients and experimental animals. Inflammation alters the expression of hepatic cytochrome P450 (CYP) enzymes, which play important roles in drug metabolism and DOX-induced toxicity. Significant sex differences have been reported in DOX-induced toxicity; however, sex differences in DOX-induced systemic inflammation and the potential effects on hepatic CYP expression have not been determined. In the current work, male and female C57Bl/6 mice were administered DOX (20 mg/kg by intraperitoneal injection), and groups of mice were sacrificed 24 and 72 h after DOX administration. DOX elicited a systemic inflammatory response in both male and female mice, but the inflammatory response was stronger in male mice. DOX altered the expression of hepatic CYP isoforms in a sex-dependent manner. Most notably, inhibition of Cyp2c29 and Cyp2e1 was stronger in male than in female mice, which paralleled the sex differences in systemic inflammation. Therefore, sex differences in DOX-induced systemic inflammation may lead to sexually dimorphic drug interactions, in addition to contributing to the previously reported sexual dimorphism in specific DOX-induced organ toxicity.

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Section: Discussionmentioning

confidence: 83%

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

Grant

Abdelgawad

Lewis

et al. 2020

IJMS

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“…findings of this study is the sex-dependent differences in cardiotoxicity and survival. Notably, clinical data showed that the male sex is a risk factor for adverse cardiac effects in adult patients undergoing anthracycline therapy (26). Consistently, regardless of genotype, male mice treated with DOX displayed an average of 45% survival rate 5 days post-DOX while in females groups an average of 86% mice survived this time period.…”

Section: Sex-dependent Differences In Doxorubicin Cardiotoxicity: Onementioning

confidence: 84%

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

George

Kiss

Obaid

et al. 2020

Preprint

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BACKGROUND: The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38 and p38, remain uncharacterized. OBJECTIVES: To determine the potential cardioprotective effects of p38 and p38 genetic deletion in mice subjected to acute DOX treatment. METHODS: Male and female wild-type (WT), p38 -/-, p38 -/-and p38 -/- -/-mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining.Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. RESULTS: Significantly improved survival was observed in p38 -/-female mice post-DOX relative to WT females, but not in p38 -/-or p38 -/- -/-male or female mice. The improved survival in DOX-treated p38 -/-females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38 -/-females. CONCLUSIONS: p38 plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38 targeting could be a potential cardioprotective strategy in anthracycline chemotherapy. NEW AND NOTEWORTHY:This study for the first time identifies the roles of the alternative p38 and p38 MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38 systemic deletion did not affect DOX-cardiotoxicity, p38 systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38-/-females and autophagy was increased.

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“…In previous studies among paediatric cancer survivors, female sex has repeatedly been associated with an increased risk of anthracycline-related LV dysfunction 31 . In adults, this relation has been inconclusive, probably because a majority of studies concerning cardiotoxicity have been performed in female breast cancer patients.…”

Section: Discussionmentioning

confidence: 95%

Cardiovascular adverse events in patients with non-Hodgkin lymphoma treated with first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP): a systematic review and meta-analysis

Linschoten

Kamphuis

Rhenen

et al. 2020

The Lancet Haematology

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Background: Patients treated for Non-Hodgkin Lymphoma's (NHL) are at risk of cardiovascular adverse events (CVAEs), with the risk of heart failure (HF) being particularly high. (R-)CHOP, the standard treatment for aggressive NHL, contains doxorubicin and cyclophosphamide, both associated with left ventricular (LV) dysfunction. The aim of this study was to delineate the cardiovascular toxicity of this regimen. Methods: We systematically searched PubMed, EMBASE, and the Cochrane Library from inception to 03/06/2019 for clinical trials and observational studies in adult NHL patients that received first-line treatment with (R-)CHOP. Studies reporting on CVAEs and treatment-related cardiovascular mortality were included. Abstracts and articles not written in English were excluded. The main outcomes were the proportion of patients with grade 3+4 CVAEs and HF. Meta-analyses of one-sample proportions were carried out. Subgroup analyses on summary estimates were performed to determine the effect of number of (R-) CHOP cycles, cycle interval, age and sex. Findings: Of 2,314 entries identified, 137 studies were eligible (median follow-up 39.0 months [IQR 25.5-52.8]). Fifty-three (39%) out of 137 studies were rated as high risk of bias for incomplete outcome data and 54 (39%) out of 137 for selective reporting. The pooled proportion for grade 3+4 CVAEs was 2.35% [95%CI 1.81-2.93](77 studies, n=14,351 patients; heterogeneity test: Q=326.21; τ 2 =0.0042; I 2 =71.40%; p< 0.001), with female sex and older age (≥65 years, RR 3.18 [95%CI 2.54; 3.98]) being associated with an increased risk. For HF (38 studies, n=5,936 patients; heterogeneity test: Q=527.33; τ 2 =0.0384; I 2 =95.05%; p<0.001), the pooled proportion was 4.62% [95%CI 2.25-7.65%], with a significant increase in reported HF from 1.64% [95%CI 0.82-2.65] to 11.72% [95%CI 3.00-24.53] when cardiac function was evaluated post-chemotherapy (p=0.017). Interpretation: The considerable increase of reported HF with cardiac monitoring, indicates that this complication often remains unnoticed. Our findings are of importance to raise the awareness of this complication among clinicians treating NHL patients and stresses the need for cardiac monitoring during-3 and post-chemotherapy. Prompt initiation of HF treatment in the pre-symptomatic phase can mitigate the progression to more advanced heart failure stages.

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Clinical and preclinical evidence of sex-related differences in anthracycline-induced cardiotoxicity

Cited by 56 publications

References 86 publications

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

Cardiovascular adverse events in patients with non-Hodgkin lymphoma treated with first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP): a systematic review and meta-analysis

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