Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Bausiene, J.
Glycine – antitumorigenic and cardioprotective substance in a model of colorectal cancer liver metastasis treatment by FOLFOX chemotherapy
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 85
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Leber Bettina
- Schemmer Peter
- Stiegler Philipp
- Altmetrics:
- Abstract:
- Colorectal cancer is among the most common cancers worldwide affecting more than 1 million people each year. About every second patient is diagnosed with distant metastases through the course of the disease with the liver being the most common site affected. Systemic chemotherapy, such as FOLFOX, is indicated prior to surgical resection to improve long-term outcomes or achieve resectability. However, chemoresistance and chemotoxicity may limit treatment efficacy. Side effects including rare, but potentially lethal and currently unavoidable cardiotoxicity have to be avoided. Glycine has been shown to have anti-tumorigenic properties in several types of cancer. Further, it reduces platelet aggregation, improves microperfusion, and has hepatoprotective and antioxidative properties. Thus, this study was conducted to test whether dietary glycine together with conventional FOLFOX chemotherapy in colorectal cancer liver metastases is oncological effective and has cardioprotective properties against chemotherapy-induced cardiotoxicity. The effect of glycine was evaluated in vitro on colorectal cancer cells (CC531) and human cardiac myocytes (HCMs). To investigate glycine in vivo, Wag/Rij rats with induced colorectal cancer liver metastases were treated with FOLFOX±5% dietary glycine. The tumors were characterized by µCT liver scans as well as immunohistochemistry including anti-Ki67 and anti-CD31 stainings. Left ventricle ejection fraction (LVEF), myocardial fibrosis and apoptosis, heart fatty acid-binding protein (h-FABP), and brain natriuretic peptide (BNP) levels were monitored. Expression of Collagen type I, II, and BNP in cardiac muscle was analysed by qPCR. The results of the study did not show any effects of glycine on CC531 and HCM viability in vitro. However, in vivo, glycine significantly decreased tumor microvascular density (MVD) by 60% (p=0.004) and tumor volume to 42-35% of that of controls (p<0.05). Furthermore, glycine did not hinder the anti-tumorigenic properties of chemotherapy. As expected, FOLFOX significantly increased h-FABP levels, myocardial fibrosis, apoptosis, and expression of the type I collagen gene. It also significantly impaired LVEF by 10% (p = 0.028). Glycine prevented chemotherapy-induced myocardial injury by reducing fibrosis degrees (p = 0.012) and apoptosis (p=0.015), and by preserving LVEF. Therefore, this study provided evidence that glycine inhibits the growth of colorectal cancer liver metastases without impairing the effectiveness of FOLFOX and prevents FOLFOX-induced heart injury. The underlying mechanisms most likely include a decreased tumor MVD. Clinical trials are necessary to implement glycine into FOLFOX treatment for colorectal cancer liver metastases.