Apoptosis induction of cardiomyocytes and subsequent fibrosis after irradiation and neoadjuvant chemotherapy

Salata, Camila; Sc, Ferreira-Machado; Andrade, Cherley Borba Vieira de; Mencalha, André Luiz; Mandarim-de-Lacerda, Carlos Alberto; Ce, de Almeida

doi:10.3109/09553002.2014.887869

Cited by 33 publications

(29 citation statements)

References 40 publications

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“…Besides the FOLFOX-induced pathologic changes in the myocardial tissue, impaired LV function was detected and the decrease of LVEF after FOLFOX correlated to h-FABP level and myocardial fibrosis. These results are in accordance with several recent preclinical studies, which also showed an increased level of apoptosis, myocardial fibrosis, and decreased LVEF after treatment with anthracycline-based chemotherapy [35][36][37][38] and with the series of reports that showed reduced LVEF following 5-FU-based chemotherapy in humans [39][40][41][42][43].…”

Section: Discussionsupporting

confidence: 92%

Dietary Glycine Prevents FOLFOX Chemotherapy-Induced Heart Injury: A Colorectal Cancer Liver Metastasis Treatment Model in Rats

et al. 2020

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Introduction: FOLFOX chemotherapy (CTx) is used for the treatment of colorectal liver metastasis (CRLM). Side effects include rare cardiotoxicity, which may limit the application of FOLFOX. Currently, there is no effective strategy to prevent FOLFOX-induced cardiotoxicity. Glycine has been shown to protect livers from CTx-induced injury and oxidative stress, and it reduces platelet aggregation and improves microperfusion. This study tested the hypothesis of glycine being cardioprotective in a rat model of FOLFOX in combination with CRLM. Materials and Methods: The effect of glycine was tested in vitro on human cardiac myocytes (HCMs). To test glycine in vivo Wag/Rij rats with induced CRLM were treated with FOLFOX ±5% dietary glycine. Left ventricle ejection fraction (LVEF), myocardial fibrosis, and apoptosis, also heart fatty acid binding protein (h-FABP) and brain natriuretic peptide levels were monitored. PCR analysis for Collagen type I, II, and brain natriuretic peptide (BNP) in the heart muscle was performed. Results: In vitro glycine had no effect on HCM cell viability. Treatment with FOLFOX resulted in a significant increase of h-FABP levels, increased myocardial fibrosis, and apoptosis as well as increased expression of type I Collagen. Furthermore, FOLFOX caused a decrease of LVEF by 10% (p = 0.028). Dietary glycine prevented FOLFOX-induced myocardial injury by preserving the LVEF and reducing the levels of fibrosis (p = 0.012) and apoptosis (p = 0.015) in vivo. Conclusions: Data presented here demonstrate for the first time that dietary glycine protects the heart against FOLFOX-induced injury during treatment for CRLM.

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Section: Discussionsupporting

confidence: 92%

Dietary Glycine Prevents FOLFOX Chemotherapy-Induced Heart Injury: A Colorectal Cancer Liver Metastasis Treatment Model in Rats

et al. 2020

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“…Although previous studies have demonstrated radiation-induced apoptosis in animal models of local heart irradiation (30, 31), we typically do not observe large numbers of apoptotic cells at the 6 month time point in experiments with local heart irradiation in rat and mouse models (18). In accordance with our previous studies, radiation did not modify the number of apoptotic cells in wild-type mice.…”

Section: Discussioncontrasting

confidence: 83%

Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model

Boerma¹,

Singh²,

Sridharan³

et al. 2015

Radiation Research

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Glutathione S-transferase alpha 4 (GSTA4-4) is one of the enzymes responsible for the removal of 4-hydroxynonenal (4-HNE), an electrophilic product of lipid peroxidation in cellular membranes during oxidative stress. 4-HNE is a direct activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor with many target genes encoding antioxidant and anti-electrophile enzymes. We have previously shown that Gsta4-null mice on a 129/Sv background exhibited increased activity of Nrf2 in the heart. Here we examined the sensitivity of this Gsta4-null mouse model towards cardiac function and structure loss due to local heart irradiation. Male Gsta4-null and wild-type mice were exposed to a single X-ray dose of 18 Gy to the heart. Six months after irradiation, immunohistochemical staining for respiratory complexes 2 and 5 indicated that radiation exposure had caused most pronounced alterations in mitochondrial morphology in Gsta4-null mice. On the other hand, wild-type mice showed a decline in cardiac function and an increase in plasma levels of troponin-I, while no such changes were observed in Gsta4-null mice. Radiation-induced Nrf2-target gene expression only in Gsta4-null mice. In conclusion, although loss of GSTA4-4 led to enhanced susceptibility of cardiac mitochondria to radiation-induced loss of morphology, cardiac function was preserved in Gsta4-null mice. We propose that this protection against cardiac function loss may occur, at least in part, by upregulation of the Nrf2 pathway.

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“…Myofibroblasts are abundant components of the reactive tumour microenvironment and are mostly accountable for the development of fibrosis [ 21 ], one of the side-effects of cancer therapy [ 31 ]. Fibroblast-to-myofibroblast differentiation increases in the stroma with age as well, resulting in an increased incidence of fibrosis-associated diseases, such as cancer [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Proteomic identification of prognostic tumour biomarkers, using chemotherapy-induced cancer-associated fibroblasts

Peiris-Pagès

Smith

Győrffy

et al. 2015

Aging

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Cancer cells grow in highly complex stromal microenvironments, which through metabolic remodelling, catabolism, autophagy and inflammation nurture them and are able to facilitate metastasis and resistance to therapy. However, these changes in the metabolic profile of stromal cancer-associated fibroblasts and their impact on cancer initiation, progression and metastasis are not well-known. This is the first study to provide a comprehensive proteomic portrait of the azathioprine and taxol-induced catabolic state on human stromal fibroblasts, which comprises changes in the expression of metabolic enzymes, myofibroblastic differentiation markers, antioxidants, proteins involved in autophagy, senescence, vesicle trafficking and protein degradation, and inducers of inflammation. Interestingly, many of these features are major contributors to the aging process. A catabolic stroma signature, generated with proteins found differentially up-regulated in taxol-treated fibroblasts, strikingly correlates with recurrence, metastasis and poor patient survival in several solid malignancies. We therefore suggest the inhibition of the catabolic state in healthy cells as a novel approach to improve current chemotherapy efficacies and possibly avoid future carcinogenic processes.

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Apoptosis induction of cardiomyocytes and subsequent fibrosis after irradiation and neoadjuvant chemotherapy

Cited by 33 publications

References 40 publications

Dietary Glycine Prevents FOLFOX Chemotherapy-Induced Heart Injury: A Colorectal Cancer Liver Metastasis Treatment Model in Rats

Dietary Glycine Prevents FOLFOX Chemotherapy-Induced Heart Injury: A Colorectal Cancer Liver Metastasis Treatment Model in Rats

Effects of Local Heart Irradiation in a Glutathione S-Transferase Alpha 4-Null Mouse Model

Proteomic identification of prognostic tumour biomarkers, using chemotherapy-induced cancer-associated fibroblasts

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