LAUSR

Abstract Caffeine is a widely consumed stimulant, known for its positive effects on physical and mental performance. These effects are potentially beneficial for ameliorating cancer-related fatigue, which affects the quality of life of patients with cancer. This study aimed to determine the anti-fatigue and antitumor effects of caffeine in tumor-bearing mice. BALB/c mice were intravenously injected with C26 colon carcinoma cells and fed with normal or 0.05% caffeine-supplemented diet. Fatigue-like behavior was assessed by running performance using a treadmill test. Lung, blood, liver, muscle, and epididymal adipose tissue samples were collected on day 13 and examined. The antitumor effect of caffeine was assessed using subcutaneous tumor-bearing mice fed with 0.05% caffeine-supplemented diet, and the tumor volume was measured. C26 tumor-bearing mice showed fatigue-like behavior associated with hypoglycemia, depleted liver glycogen and non-esterified fatty acid (NEFA) levels. C26 tumor-bearing mice fed with 0.05% caffeine-supplemented diet showed improved running performance associated with restored NEFA levels. However, exacerbated hypoglycemia and liver glycogen levels after caffeine consumption may be due to tumor-induced catabolic signals, as the tumor volume was not affected. Collectively, caffeine may exert anti-fatigue effects through enhanced lipolysis leading to restored NEFA levels, which can be used as an alternative energy source.