Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats

Abstract

The purpose of this study was to investigate (1) the impact of tumor growth on homocysteine (Hcy) metabolism, liver oxidative stress and cancer cachexia and, (2) the potential benefits of creatine supplementation in Walker-256 tumor-bearing rats. Three experiments were conducted. First, rats were killed on days 5 (D5), 10 (D10) and 14 (D14) after tumor implantation. In experiment 2, rats were randomly assigned to three groups designated as control (C), tumor-bearing (T) and tumor-bearing supplemented with creatine (TCr). A life span experiment was conducted as the third experiment. Creatine was supplied in drinking water for 21 days (8 g/L) in all cases. Tumor implantation consisted of a suspension of Walker-256 cells (8.0 × 10(7) cells in 0.5 mL of PBS). The progressive increase (P < 0.05) in tumor mass coincided with a progressively lower body weight and higher hepatic oxidative stress; plasma Hcy concentration was 80 % higher (P < 0.05) by 10 days of tumor implantation. Impaired Hcy metabolism was evidenced by decreased hepatic betaine-homocysteine methyltransferase (Bhmt), glycine N-methyltransferase (Gnmt) and cystathionine beta synthase (CBS) gene expression. In contrast, creatine supplementation promoted a 28 % reduction of tumor weight (P < 0.05). Plasma Hcy (C 6.1 ± 0.6, T 10.3 ± 1.5, TCr 6.3 ± 0.9, µmol/L) and hepatic oxidative stress were lower in the TCr group compared to T. Creatine supplementation was unable to decrease Hcy concentration and to increase SAM/SAH ratio in tumor tissue. These data suggest that creatine effects on hepatic impaired Hcy metabolism promoted by tumor cell inoculation are responsible to decrease plasma Hcy in tumor-bearing rats. In conclusion, Walker-256 tumor growth is associated with progressive hyperhomocysteinemia, body weight loss and liver oxidative stress in rats. Creatine supplementation, however, prevented these tumor-associated perturbations.

International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine

“…In this regard, creatine supplementation has been reported to help lower cholesterol and triglyceride levels [67, 196]; reduce fat accumulation in the liver [197]; reduce homocysteine levels [198]; serve as an antioxidant [199–202]; enhance glycemic control [132, 203–205]; slow tumor growth in some types of cancers [32, 198, 206, 207]; increase strength and/or muscle mass [37, 41, 44, 45, 82, 208–212]; minimize bone loss [211, 212]; improve functional capacity in patients with knee osteoarthritis [213] and fibromyalgia [214]; positively influence cognitive function [43, 83, 195]; and in some instances, serve as an anti-depressant [215–217]. …”

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

“…The mechanisms underlying spontaneous regression are not entirely clear but may involve development of an adaptive immune response (Pardoll and Topalian, 1998; Rees and Mian, 1999), differential propagation of tumor sub clones in their microenvironment (Khong and Restifo, 2002) and consequent elimination by immune cells, antibodies, cytokines, and chemokines (Dunn et al, 2002, 2006; Bui and Schreiber, 2007; Jaganjac et al, 2008). Physical activity of the animals, exercise (Hoffman et al, 1962; Deminice et al, 2016b), dietary factors (Bekesi and Winzler, 1970; Kwong et al, 1984; Luty et al, 2016), or hormonal levels (Khegai, 2013; Khegay and Ivanova, 2015) may influence the regression of these cells or inhibit the activities driven by these cells (Campos-Ferraz et al, 2016; Cruz et al, 2016; Deminice et al, 2016a; Fracaro et al, 2016; Toneto et al, 2016). In most studies, tumor regression is generally overlooked as the tumor-bearing rats are sacrificed before regression is evident (Guimarães et al, 2010).…”

Creatine: a miserable life without it

“…BB-CK, found to be important for the energetics of cell division and cell cycle control, may thus also be involved in cancer cell progression and metastasis. Down-regulation or inhibition of CK by inhibitors or siRNA appears to retard mitosis, promote apoptosis and reduce metastasis, whereas creatine supplementation itself has now been convincingly shown to provide anti-cancer effects (Campos Ferraz et al 2016;Deminice et al 2016a;Pal et al 2016). …”

“…In addition, creatine treatment led to a reduction in plasma Hcy concentrations and hepatic oxidative stress in the tumor-bearing animals (Deminice et al 2016a). Thus, again, the anti-cancer and anti-cachexia effects observed in this experimental animal cancer model simply by supplementation of creatine-which is an efficient and safe nutritional supplement also for humans-will justify further work along these lines, eventually testing creatine supplementation in clinical cancer trials.…”