Dietary Melatonin and Glycine Decrease Tumor Growth through Antiangiogenic Activity in Experimental Colorectal Liver Metastasis

Abstract

Despite multimodal treatment strategies, clinical outcomes of advanced stage colorectal cancer (CRC) patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Since both melatonin and glycine have anti-cancer activities without relevant side effects, this study was designed to investigate their combined effects in experimental CRC liver metastases. CRC metastasis with CC531 cells were induced in male Wistar rats. Melatonin and glycine alone or their combination were supplemented for 14 days (n = 100). Blood parameters, a micro-computed tomography scan (tumor volume over time), and immunohistochemistry for Ki67 and CD31 expression in tumor tissue were compared between groups. Melatonin and glycine alone significantly reduced the tumor volume by 63.2% (p = 0.002) and 43% (p = 0.044) over time, respectively, while tumor volume increased by 8.7% in the controls. Moreover, treatment with melatonin and glycine alone reduced the tumor proliferation index. Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters. The leukocyte count was significantly increased with melatonin at the end of the experiment (p = 0.012) which was due to a high lymphocytes count. Tumor microvascular density was significantly reduced in all treatment groups. The results of this study suggest an inhibitory function for melatonin and glycine alone in the case of CRC liver metastasis growth by acting as natural antiangiogenic molecules, followed by angiogenesis-dependent cancer proliferation and immunomodulation.

Melatonin and Glycine Reduce Uterus Ischemia/Reperfusion Injury in a Rat Model of Warm Ischemia

“…Two hours prior to IRI or sham procedure, the melatonin and combined treatment groups received 1.5 mL of milk (3.5% fat) containing 50 mg/kg melatonin (Sigma-Aldrich, St. Louis, MO, USA) via gavage, while the control and glycine groups received the same type of milk containing a corresponding amount of microcrystalline cellulose (placebo; from Sigma-Aldrich, St. Louis, MO, USA). The administration route and dose of both investigated substances (melatonin and glycine) were adopted based on previous experiments [27,28,40,44,53,54]. Water consumption, food intake and body weight were recorded regularly (for details, see Figure 5).…”

Probiotic Supplementation Suppresses Tumor Growth in an Experimental Colorectal Cancer Liver Metastasis Model

“…For several years our study group has been investigating different cancer-suppressing agents in an orthotopic CRCLM rat model. We have previously determined that both glycine and melatonin substantially suppress CRCLM growth in vivo [ 29 , 30 ]. Currently, we are conducting a similar study looking into possible combinations of these novel tumor-suppressing agents and their possible synergistic effects.…”

“…The FOLFOX CTx regimen was chosen in this experiment due to its proven potency in treating CRCLM [ 32 , 33 ]. This regimen was also used in another similar study by our research group with the desired tumor suppressive effect [ 29 , 30 ]. On day 28 a mixture of 100 mg/m 2 Calcium folinate (Sandoz, Holzkirchen, Germany), 42.5 mg/m 2 Oxaliplatin (Fresenius Kabi, Bad Homburg, Germany) and 500 mg/m 2 5-Fluoruracil (Sandoz, Holzkirchen, Germany) was used.…”

The mechanisms and roles of melatonin in gastrointestinal cancer

“…Collin et al confirmed that menadione plus melatonin on Caco-2 cells could reduce cell proliferation, induce reactive nitrogen species formation, enhance superoxide anion content, and increase catalase activity, suggesting the potential as adjuvant therapy for CRC acting on different oncogenic pathways (85). Kvietkauskas et al designed a study to explore the combined role of melatonin and glycine in CRC liver metastasis (86). They found that supplementation with melatonin and glycine reduce CRC liver metastasis growth by acting as natural antiangiogenic molecules.…”

“…Kvietkauskas et al. designed a study to explore the combined role of melatonin and glycine in CRC liver metastasis ( 86 ). They found that supplementation with melatonin and glycine reduce CRC liver metastasis growth by acting as natural antiangiogenic molecules.…”