Exploratory studies of the potential anti-cancer effects of creatine

Abstract

Two experiments were performed, in which male Wistar Walker 256 tumor-bearing rats were inoculated with 4 × 10(7) tumor cells subcutaneously and received either creatine (300 mg/kg body weight/day; CR) or placebo (water; PL) supplementation via intragastric gavage. In experiment 1, 50 rats were given PL (n = 22) or CR (n = 22) and a non-supplemented, non-inoculated group served as control CT (n = 6), for 40 days, and the survival rate and tumor mass were assessed. In experiment 2, 25 rats were given CR or PL for 15 days and sacrificed for biochemical analysis. Again, a non-supplemented, non-inoculated group served as control (CT; n = 6). Tumor and muscle creatine kinase (CK) activity and total creatine content, acidosis, inflammatory cytokines, and antioxidant capacity were assessed. Tumor growth was significantly reduced by approximately 30 % in CR when compared with PL (p = 0.03), although the survival rate was not significantly different between CR and PL (p = 0.65). Tumor creatine content tended to be higher in CR than PL (p = 0.096). Tumor CK activity in the cytosolic fraction was higher in CR than PL (p < 0.0001). Blood pCO2 was higher in CT and CR than PL (p = 0.0007 and p = 0.004, respectively). HCO3 was augmented in CT compared to PL (p = 0.03) and CR (p = 0.001). Plasma IL-6 was lower and IL-10 level was higher in CR than PL (p = 0.03 and p = 0.0007, respectively) and TNF-alpha featured a tendency of decrease in CR compared to PL (p = 0.08). Additionally, total antioxidant capacity tended to be lower in CT than PL (p = 0.07). Creatine supplementation was able to slow tumor growth without affecting the overall survival rate, probably due to the re-establishment of the CK-creatine system in cancer cells, leading to attenuation in acidosis, inflammation, and oxidative stress. These findings support the role of creatine as a putative anti-cancer agent as well as help in expanding our knowledge on its potential mechanisms of action in malignancies.

MicroRNA-Mediated Metabolic Reprograming in Renal Cancer

“…Suppressed expression of GATM in RCC tumors [4] is in line with recent findings of decreased excretion of guanidinoacetate (GAA) in RCC patients [21]. Interestingly, several studies have demonstrated that creatine inhibits growth of tumor cells both in vitro and in vivo [22][23][24]. The exact mechanism by which creatine attenuates cancer growth is unknown; however, possible mechanisms include inhibition of glycolysis or generation of acidosis [25].…”

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

“…ATP and PCr can then diffuse back into the cytosol and help buffer energy needs. This coupling also reduces the formation of reactive oxygen species (ROS) and can therefore act as a direct and/or indirect antioxidant [32–35]. The CK/PCr energy shuttle thereby connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) in order to fuel energy metabolism [24, 25, 27].…”

“…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).…”