Abstract
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.
Highlights
FOLFOX chemotherapy (CTx) is used for the treatment of colorectal liver metastasis (CRLM)
This study aimed to demonstrate the cardioprotective potential of glycine on rats suffering from CRLM and treated with a single cycle of FOLFOX CTx
Animals were not affected by study-related procedures, other than FOLFOX, which resulted in diarrhea and weight loss
Summary
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. There is no effective strategy to prevent FOLFOX-induced cardiotoxicity. This study tested the hypothesis of glycine being cardioprotective in a rat model of FOLFOX in combination with CRLM. FOLFOX, which consists of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (OX) is proven to be effective for colorectal cancer liver metastasis (CRLM) treatment [4]. The reported incidence of 5-FU-induced cardiotoxicity varies between 1% and 68% for various solid cancers [6,7,8], with a rate of 8.5% in a specific colorectal cancer patients cohort [9]. As FOLFOX-induced cardiotoxicity can cause irreversible damage to the myocardium, preventive strategies are mandatory
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