Abstract
Chemotherapy-induced cardiovascular toxicity (CICT) is a well-established risk for cancer survivors and causes diseases such as heart failure, arrhythmia, vascular dysfunction, and atherosclerosis. As our knowledge of the precise cardiovascular risks of each chemotherapy agent has improved, it has become clear that genomics is one of the most influential predictors of which patients will experience cardiovascular toxicity. Most recently, GWAS-led, top-down approaches have identified novel genetic variants and their related genes that are statistically related to CICT. Importantly, the advent of human-induced pluripotent stem cell (hiPSC) models provides a system to experimentally test the effect of these genomic findings in vitro, query the underlying mechanisms, and develop novel strategies to mitigate the cardiovascular toxicity liabilities due to these mechanisms. Here we review the cardiovascular toxicities of chemotherapy drugs, discuss how these can be modeled in vitro, and suggest how these models can be used to validate genetic variants that predispose patients to these effects.
PMID: 32078739 [PubMed - as supplied by publisher]
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Long-term survivors of early breast cancer treated with chemotherapy are characterized by a pro-inflammatory biomarker profile compared to matched controls.
Long-term survivors of early breast cancer treated with chemotherapy are characterized by a pro-inflammatory biomarker profile compared to matched controls.
Eur J Heart Fail. 2020 Feb 20;:
Authors: Tromp J, Boerman LM, Sama IE, Maass SWMC, Maduro JH, Hummel YM, Berger MY, de Bock GH, Gietema JA, Berendsen AJ, van der Meer P
Abstract
BACKGROUND: Chemo- and radiotherapy for breast cancer (BC) can lead to cardiotoxicity even years after the initial treatment. The pathophysiology behind these late cardiac effects is poorly understood. Therefore, we studied a large panel of biomarkers from different pathophysiological domains in long-term BC survivors, and compared these to matched controls.
METHODS AND RESULTS: In total 91 biomarkers were measured in 688 subjects: 342 BC survivors stratified either to treatment with chemotherapy ± radiotherapy (n = 170) or radiotherapy alone (n = 172) and matched controls. Mean age was 59 ± 9 years and 65 ± 8 years for women treated with chemotherapy ± radiotherapy and radiotherapy alone, respectively, with a mean time since treatment of 11 ± 5.5 years. No biomarkers were differentially expressed in survivors treated with radiotherapy alone vs. controls (P for all >0.1). In sharp contrast, a total of 19 biomarkers were elevated, relative to controls, in BC survivors treated with chemotherapy ± radiotherapy after correction for multiple comparisons (P <0.05
CONCLUSION: Breast cancer survivors treated with chemotherapy ± radiotherapy show a distinct biomarker profile associated with mild cardiac dysfunction even 10 years after treatment. These results suggest that an ongoing pro-inflammatory state and activation of matrix metalloproteinases following initial treatment with chemotherapy might play a role in the observed cardiac dysfunction in late BC survivors.
PMID: 32078215 [PubMed - as supplied by publisher]
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Doxorubicin induces cardiomyocyte apoptosis and atrophy through cyclin-dependent kinase 2-mediated activation of forkhead box O1.
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Doxorubicin induces cardiomyocyte apoptosis and atrophy through cyclin-dependent kinase 2-mediated activation of forkhead box O1.
J Biol Chem. 2020 Feb 19;:
Authors: Xia P, Chen J, Liu Y, Fletcher M, Jensen BC, Cheng Z
Abstract
Recent clinical investigations indicate that anthracycline-based chemotherapies induce early declines in heart mass in cancer patients. Heart mass decline may be caused by a decrease in cardiac cell number due to increased cell death, or by a reduction in cell size due to atrophy. We previously reported that an anthracycline, doxorubicin (DOX), induces apoptotic death of cardiomyocytes by activating cyclin-dependent kinase 2 (CDK2). However, the signaling pathway downstream of CDK2 remains to be characterized, and it is also unclear whether the same pathway mediates cardiac atrophy. Here, we demonstrate that DOX exposure induces CDK2-dependent phosphorylation of the transcription factor forkhead box O1 (FOXO1) at Ser-249, leading to transcription of its pro-apoptotic target gene, Bcl-2-interacting mediator of cell death (Bim). In cultured cardiomyocytes, treatment with the FOXO1 inhibitor AS1842856 or transfection with FOXO1-specific siRNAs protected against DOX-induced apoptosis and mitochondrial damage. Oral administration of AS1842856 in mice abrogated apoptosis and prevented DOX-induced cardiac dysfunction. Intriguingly, the pharmacological FOXO1 inhibition also attenuated DOX-induced cardiac atrophy, likely due to repression of muscle RING finger 1 (MuRF1), a pro-atrophic FOXO1 target gene. In conclusion, DOX exposure induces CDK2-dependent FOXO1 activation, resulting in cardiomyocyte apoptosis and atrophy. Our results identify FOXO1 as a promising drug target for managing DOX-induced cardiotoxicity. We propose that FOXO1 inhibitors may have potential as cardioprotective therapeutics during cancer chemotherapy.
PMID: 32075913 [PubMed - as supplied by publisher]
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Rosmarinic Acid as a Candidate in a Phenotypic Profiling Cardio-/Cytotoxicity Cell Model Induced by Doxorubicin.
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Rosmarinic Acid as a Candidate in a Phenotypic Profiling Cardio-/Cytotoxicity Cell Model Induced by Doxorubicin.
Molecules. 2020 Feb 14;25(4):
Authors: Zhang Q, Li J, Peng S, Zhang Y, Qiao Y
Abstract
Advances in cancer treatment have led to significant improvements in long-term survival in many types of cancer, but heart dysfunction and heart failure, associated with cancer treatment, have also increased. Anthracyclines are the main cause of this type of cardiotoxicity. In this study, we describe a combined experimental and cell morphology analysis approach for the high-throughput measurement and analysis of a cardiomyocyte cell profile, using partial least square linear discriminant analysis (PLS-LDA) as the pattern recognition algorithm. When screening a small-scale natural compound library, rosmarinic acid (RosA), as a candidate drug, showed the same cardioprotective effect as the positive control. We investigated the protective mechanism of RosA on a human cardiomyocyte cell line (AC16) and human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We showed that RosA pretreatment suppressed doxorubicin (Dox)-induced cell apoptosis and decreased the activity of caspase-9. RosA promotes the expression of Heme oxygenase-1 (HO-1) and reduces the production of reactive oxygen species (Ros), which is induced by Dox. Meanwhile, it can also promote the expression of cardiac-development-related protein, including histone deacetylase 1 (HDAC1), GATA binding protein 4 (GATA4) and troponin I3, cardiac type (CTnI). Collectively, our data support the notion that RosA is a protective agent in hiPSC-CMs and has the potential for therapeutic use in the treatment of cancer therapy-related cardiac dysfunction and heart failure.
PMID: 32075047 [PubMed - in process]
22 February 2020
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Angiotensin-(1-7) reduces doxorubicin-induced cardiac dysfunction in male and female Sprague-Dawley rats through antioxidant mechanisms.
Angiotensin-(1-7) reduces doxorubicin-induced cardiac dysfunction in male and female Sprague-Dawley rats through antioxidant mechanisms.
Am J Physiol Heart Circ Physiol. 2020 Feb 21;:
Authors: Rahimi O, Kirby J, Varagic J, Westwood BM, Tallant EA, Gallagher PE
Abstract
Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality-of-life in pediatric cancer patients. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass and the addition of Ang-(1-7) had no effect. However, adjunct Ang-(1-7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak (E) (p<0.05)<0.001)<0.001),<0.05),<0.001)<0.001),<0.05;<0.01)<0.05)
PMID: 32083974 [PubMed - as supplied by publisher]
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Reactive oxygen species (ROS)-responsive polymersomes with site-specific chemotherapeutic delivery into tumors via spacer design chemistry.
Reactive oxygen species (ROS)-responsive polymersomes with site-specific chemotherapeutic delivery into tumors via spacer design chemistry.
Biomacromolecules. 2020 Feb 21;:
Authors: Jager E, Sincari V, Albuquerque LJC, Jager A, Humajova J, Kucka J, Pankrac J, Paral P, Heizer T, Janoušková O, Konefal R, Pavlova E, Sedlacek O, Giacomelli FC, Pouckova P, Sefc L, Stepanek P, Hruby M
Abstract
The lack of cellular and tissue specificity in conventional chemotherapies along with the generation of a complex tumor microenvironment (TME) limit the dosage of active agents that reaches tumor sites thereby resulting in ineffective responses and side effects. Therefore, the development of selective TME responsive nanomedicines is of due relevance towards successful chemotherapies, albeit challenging. In this framework, we have synthesized novel, ready-to-use ROS-responsive amphiphilic block copolymers (BCs) with two different spacer chemistry designs to connect a hydrophobic boronic ester-based ROS sensor into the polymer backbone. Hydrodynamic flow focusing nanoprecipitation microfluidics (MF) was used in the preparation of well-defined ROS-responsive PSs there were further characterized by a combo of techniques (1H NMR, DLS, SLS, TEM and cryo-TEM). The reaction with hydrogen peroxide releases an amphiphilic phenol or a hydrophilic carboxylic acid which impacts polymersome (PS) stability and cargo release. Therefore, the importance of the spacer chemistry in BCs deprotection and PSs stability and cargo release is herein highlighted. We have also evaluated the impact of spacer chemistry on PS-specific release of the chemotherapeutic drug doxorubicin (DOX) into tumors in vitro and in vivo. We demonstrate that by spacer chemistry design one can enhance the efficacy of DOX treatments (decrease in tumor growth and prolonged animal survival) in mice bearing EL4 T cell lymphoma. Side effects (weight loss and cardiotoxicity) were also reduced compared to free DOX administration highlighting the potential of the well-defined ROS-responsive PSs as TME selective nanomedicines. The PSs could also find applications in other environments with high ROS-levels, such as, for instance, chronic inflammations, aging, diabetes, cardiovascular diseases and obesity.
PMID: 32083473 [PubMed - as supplied by publisher]
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Targeting MDR-1 gene expression, BAX/BCL2, caspase-3 and Ki-67 by nano-encapsulated imatinib and hesperidin to enhance anticancer activity and ameliorate cardiotoxicity.
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