Abstract
BACKGROUND: The current investigation examined the association between chemotherapy and/or radiotherapy and subsequent risk of cardiovascular disease (CVD) in breast cancer survivors.
METHODS: A case-cohort study was conducted, based on 2165 female breast cancer survivors recruited from "Leumit" healthcare fund, who were diagnosed with primary nonmetastatic invasive breast cancer between 2002 and 2012. A 20% random subcohort was sampled at baseline, and all CVD cases were identified. Adjusted hazard ratios (HRs) with 95% confidence intervals (CI) were estimated by weighted Cox proportional hazards models.
RESULTS: Of 2165 breast cancer survivors, 466 developed CVD over a mean follow-up of 5.7 years. The crude cumulative incidence of CVD accounting for death as a competing risk was 33.6% (95% CI, 29.6-37.6%) at 13 years of follow-up. Lifestyle components, collected post-CVD incidence, indicated a higher prevalence of poor nutrition and physical inactivity in CVD patients. In multivariable analyses, CVD was positively associated with radiotherapy without chemotherapy compared to no radiotherapy or chemotherapy (HR, 2.94; 95% CI, 1.17-7.38; p=.022), outpatient visits (HR per average 10-annual visits, 1.86; 95% CI, 1.50-2.31; p<.001),<.001),
CONCLUSIONS: Radiotherapy administered as an adjuvant treatment for breast cancer elevates the risk of CVD. Preventive strategies should be directed to surveillance for radiotherapy-related CVD dysfunction. Efforts should also address lifestyle modifications and occupational rehabilitation in patients at a high risk of CVD.
PMID: 30587455 [PubMed - indexed for MEDLINE]
11 May 2020
10:31
Cardiotoxicity News
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Crocin protects against cardiotoxicity induced by doxorubicin through TLR-2/NF-κB signal pathway in vivo and vitro.
Crocin protects against cardiotoxicity induced by doxorubicin through TLR-2/NF-κB signal pathway in vivo and vitro.
Int Immunopharmacol. 2020 May 06;84:106548
Authors: Chu X, Zhang Y, Xue Y, Li Z, Shi J, Wang H, Chu L
Abstract
Doxorubicin (DOX) is widely used to treat multiple of tumors, but its clinical trials are allied with some serious adverse events mainly cardiac functional abnormalities. So the objective of our investigation is to identify the cardioprotective action of crocin (CRO), a natural compound derived from saffron, against DOX-induced cardiotoxicity. CRO was injected intraperitoneally (i.p.) to rats for sixconsecutive days and DOX (i.p.) was administered on the fourth day. H9c2 cells were treated with DOX for 24 h after being pre-treated by CRO for 2 h. CROreduced tachycardiaand J-point elevation,decreased the levelsof serum creatine kinase, lactate dehydrogenase,glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase.CRO exerted positive effect on DOX-induced ROS productionand changes of oxidative stress biomarkers. CRO significantlydecreased intracellular Ca2+ concentration andincreased mitochondria membrane potentialin H9c2 cells. CRO also resisted the DOX-induced high expressionof tumor necrosis factor-αand interleukin-6, inhibitedapoptosisand improved the abnormal expression levels of Bcl-2, Bax and Caspase-3 proteins.CRO obviously restrained DOX-mediatedhigh expression of toll-like receptor-2 (TLR-2) and nuclear factor kappa-B (NF-κB) in ventricular tissue. Inbrief,CRO distinctly restrained DOX-mediated cardiotoxicity by inhibiting oxidative stress, inflammation, apoptoticandredressingcardiomyocyte calcium dyshomeostasis and mitochondria damage.These cardioprotective effects may berelated closely with the TLR2/NF-κB pathway.
PMID: 32388215 [PubMed - as supplied by publisher]
12 May 2020
11:00
Cardiotoxicity News
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The Tumor-Suppressive Human Circular RNA CircITCH Sponges miR-330-5p to Ameliorate Doxorubicin-Induced Cardiotoxicity Through Upregulating SIRT6, Survivin, and SERCA2a.
The Tumor-Suppressive Human Circular RNA CircITCH Sponges miR-330-5p to Ameliorate Doxorubicin-Induced Cardiotoxicity Through Upregulating SIRT6, Survivin, and SERCA2a.
Circ Res. 2020 May 11;:
Authors: Han D, Wang Y, Zhang J, Dai X, Zhou T, Chen J, Tao B, Wang Y, Cao F
Abstract
Rationale: Doxorubicin (DOX) is one of the most potent antitumor agents available; however, its clinical use is restricted because it poses a risk of severe cardiotoxicity. Previous work has established that CircITCH is a broad-spectrum tumor-suppressive circular RNA and that its host gene, ITCH, is involved in doxorubicin-induced cardiotoxicity (DOXIC). Whether CircITCH plays a role in DOXIC remains unknown. Objective: We aimed to dissect the role of CircITCH in DOXIC and further decipher its potential mechanisms. Methods and Results: Circular RNA sequencing was performed to screen the potentially involved circRNAs in doxorubicin-induced cardiotoxicity pathogenesis. Quantitative PCR (qPCR) and RNA ISH (in situ hybridization) revealed that CircITCH was downregulated in DOX-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in the autopsy specimens from cancer patients who suffered from DOX-induced cardiomyopathy. Cell death/viability assays, detection of cardiomyocyte necrosis markers, microelectrode array, and cardiomyocyte functional assays revealed that CircITCH ameliorated DOX-induced cardiomyocyte injury and dysfunction. Detection of cellular/mitochondrial oxidative stress and DNA damage markers verified that CircITCH alleviated cellular/mitochondrial oxidative stress and DNA damage induced by DOX. RNA pull-down assays, Ago2 immunoprecipitation and double fluorescent ISH (FISH) identified miR-330-5p as a direct target of CircITCH. Moreover, CircITCH was found to function by acting as an endogenous sponge that sequestered miR-330-5p. Bioinformatic analysis, luciferase reporter assays and qPCR showed that SIRT6, BIRC5 (Survivin) and ATP2A2 (SERCA2a) were direct targets of miR-330-5p and that they were regulated by the CircITCH/miR-330-5p axis in DOXIC. Further experiments demonstrated that CircITCH-mediated alleviation of DOXIC was dependent on the interactions between miR-330-5p and the 3´-UTRs of SIRT6, BIRC5 and ATP2A2 mRNA. Finally, AAV9 vector-based overexpression of the well-conserved CircITCH partly prevented DOXIC in mice. Conclusions: CircITCH represents a novel therapeutic target for DOXIC because it acts as a natural sponge of miR-330-5p, thereby upregulating SIRT6, Survivin and SERCA2a to alleviate DOX-induced cardiomyocyte injury and dysfunction.
PMID: 32392088 [PubMed - as supplied by publisher]
11:00
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Protective role of p53 in doxorubicin-induced cardiomyopathy as a mitochondrial disease.
Protective role of p53 in doxorubicin-induced cardiomyopathy as a mitochondrial disease.
Mol Cell Oncol. 2020;7(3):1724598
Authors: Nishi M, Wang PY, Hwang PM
Abstract
Doxorubicin is widely used against cancer but carries the risk of a progressive cardiomyopathy associated with mitochondrial loss. Using genetic models, our recent study demonstrates that mitochondrial genomic DNA regulation by tumor protein p53 (TP53, best known as p53) prevents the cardiotoxicity of low dose doxorubicin which does not activate the p53-dependent cell death pathway.
PMID: 32391420 [PubMed]
11:00
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Doxorubicin-induced oxidative stress differentially regulates proteolytic signaling in cardiac and skeletal muscle.
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Doxorubicin-induced oxidative stress differentially regulates proteolytic signaling in cardiac and skeletal muscle.
Am J Physiol Regul Integr Comp Physiol. 2020 02 01;318(2):R227-R233
Authors: Montalvo RN, Doerr V, Min K, Szeto HH, Smuder AJ
Abstract
Doxorubicin (DOX) is a highly effective antineoplastic agent used in cancer treatment. Unfortunately, clinical use of DOX is limited due to the development of dose-dependent toxicity to cardiac and respiratory (i.e., diaphragm) muscles. After administration, DOX preferentially localizes to the inner mitochondrial membrane, where it promotes cellular toxicity via enhanced mitochondrial reactive oxygen species (ROS) production. Although recent evidence suggests that amelioration of mitochondrial ROS emission preserves cardiorespiratory muscle function following DOX treatment, the mechanisms responsible for this protection remain unknown. Therefore, we tested the hypothesis that DOX-induced mitochondrial ROS production is required to stimulate pathological signaling by the autophagy/lysosomal system (ALS), the ubiquitin-proteasome pathway (UPP), and the unfolded protein response (UPR). Cause and effect were determined by administration of the mitochondria-targeted peptide SS-31 to DOX-treated animals. Interestingly, while SS-31 abrogated aberrant ROS emission in cardiorespiratory muscles of DOX-treated animals, our results revealed muscle-specific regulation of effector pathways. In the heart, SS-31 prevented DOX-induced proteolytic signaling through the ALS and UPP. In contrast, ALS signaling was inhibited by SS-31 in the diaphragm, but the UPP was not affected. UPR signaling was activated in both muscles at eukaryotic translation initiation factor 2α (eIF2α) S51 in the heart and diaphragm of DOX-treated animals and was attenuated with SS-31 treatment in both tissues. However, downstream signaling of eIF2α (activating transcription factor 4 and CCAAT/enhancer-binding protein homologous protein) was diminished in the heart but upregulated in the diaphragm with DOX. Collectively, these results show that DOX-induced ROS production plays distinct roles in the regulation of cardiac and diaphragm muscle proteolysis.
PMID: 31774307 [PubMed - indexed for MEDLINE]
11:00
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Cardio-oncology: a novel platform for basic and translational cardiovascular investigation driven by clinical need.
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Cardio-oncology: a novel platform for basic and translational cardiovascular investigation driven by clinical need.
Cardiovasc Res. 2019 04 15;115(5):819-823
Authors: Moslehi J, Fujiwara K, Guzik T
PMID: 30888396 [PubMed - indexed for MEDLINE]
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Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--academic.oup.com-images-oup_pubmed.png //www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.ncbi.nlm.nih.gov-corehtml-pmc-pmcgifs-pubmed-pmc.png Related Articles
Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury.
Cardiovasc Res. 2019 04 15;115(5):978-988
Authors: Neves KB, Rios FJ, Jones R, Evans TRJ, Montezano AC, Touyz RM
Abstract
Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO- levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.
PMID: 30753341 [PubMed - indexed for MEDLINE]
11:00
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New avenues in cardio-oncology.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.impactaging.com-resources-Aging_FreeFullText.gif //www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.ncbi.nlm.nih.gov-corehtml-pmc-pmcgifs-pubmed-pmc.png Related Articles
New avenues in cardio-oncology.
Aging (Albany NY). 2019 02 06;11(4):1075-1076
Authors: Sala V, Li M, Ghigo A
PMID: 30728321 [PubMed - indexed for MEDLINE]
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T cell checkpoint regulators in the heart.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--academic.oup.com-images-oup_pubmed.png //www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.ncbi.nlm.nih.gov-corehtml-pmc-pmcgifs-pubmed-pmc.png Related Articles
T cell checkpoint regulators in the heart.
Cardiovasc Res. 2019 04 15;115(5):869-877
Authors: Grabie N, Lichtman AH, Padera R
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