The History Regarding Bleomycin

We have PRDX4 previously established that rapamycin (a selective mTOR inhibitor), and metformin (an indirect inhibitor of mTOR signaling through its effects on gluconeogenesis and associated activation of AMPK-regulated signals), partially mimic the tumor inhibitory effects of CR on transplanted pancreatic tumor growth [13]. Branched-chain amino acids (BCAAs), which account for over 20% of total dietary protein intake, are known activators of the mTOR pathway in muscle and epithelial tissues [14-16]. Of the three BCAAs, leucine exerts the most potent effect on mTOR activation and enhancement of protein synthesis in various tissues, including skeletal muscle [17,18]. Athletes commonly use leucine supplementation to Bleomycin supplier activate mTOR-regulated protein synthesis and accelerate muscle repair and regeneration after injuries or intense bouts of exercise [19]. Leucine supplementation is also increasingly being recommended to reduce the muscle wasting that occurs with cancer cachexia [20]. Cachexia is characterized by involuntary weight loss and muscle wasting, is associated with increased morbidity and mortality, and frequently occurs in pancreatic cancer patients [21]. Increased muscle protein synthesis in response to leucine-induced mTOR activation has been shown to inhibit muscle wasting in mouse models of cancer cachexia and in cancer patients [22-25]. However, the rates of protein synthesis increase to a much greater extent in tumors than in muscle [24], suggesting that while leucine supplementation may protect against cancer-associated cachexia, it may also enhance the progression of the cancer. Unfortunately, studies of the effects of leucine supplementation on cancer are limited. Long-term leucine supplementation (2% of diet, w/w) promoted bladder cancer development in rats Duvelisib treated with a known bladder carcinogen [26,27], but no studies have connected leucine supplementation with tumor growth. In the present study, we tested the effect of leucine supplementation on transplanted Panc02 mouse pancreatic cancer growth and mTOR signaling in the context of lean mice (fed a CR diet regimen) or overweight mice (fed a high calorie control diet regimen). Our findings suggest that leucine enhances pancreatic tumor progression in lean and overweight mice, and the underlying mechanisms may differ by weight status. Methods Mice and dietary interventions All experiments were conducted under a protocol approved by the Institutional Animal Care and Use Committee at the University of Texas at Austin. Eighty-eight male C57BL/6 mice were obtained from Charles River Breeding Laboratories (Wilmington, MA, USA) at 6 to 8 weeks of age, and upon arrival were singly-housed in a semibarrier facility at the University of Texas at Austin Animal Resource Center and fed a chow diet during a one-week acclimation period.