Abstract
Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors.
Highlights
Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood
We investigated whether the fasting/fastingmimicking diet (FMD) potentiates the anticancer effect of vitamin C against different KRAS-mutant cancer models
Human (HCT116, DLD-1) and murine (CT26) KRASmutant colorectal cancer (CRC) cell lines, as well as KRAS-mutant lung cancer (H23, H727) and pancreatic ductal adenocarcinoma (PANC1) cells, were grown in control medium (1 g/L glucose and 10% serum; CTR) or in a FMD-like medium (0.5 g/L glucose and 1% serum), here referred to as short-term starvation condition (STS), which mimics the reduction of extracellular glucose and growth factor concentrations that occurs during prolonged (>48 h) fasting or FMD in vivo, with or without pharmacological concentrations of vitamin C (≥0.3 mM)
Summary
Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. High-dose vitamin C can exert its anticancer effects by pro-oxidant reactions, which cause the formation of hydrogen peroxide and hydroxyl radicals via Fenton chemistry These reactive oxygen species (ROS) cause damage to macromolecules, thereby leading to cell death[3,4,6,7,8]. RAS oncogenic activation further increases cellular iron content by upregulating iron-uptake proteins, such as transferrin receptor (Trf1), and by downregulating iron export and storage proteins, in particular ferritin[10,11,12] In this context, the stress inducible protein heme-oxygenase-1 (HO-1), regulates ferritin expression to avoid an excessive free iron content, which can damage macromolecules[15]. We have previously shown that fasting or a fastingmimicking diet (FMD) reduce tumor progression and sensitize different types of cancer to chemotherapy, while protecting normal cells from chemo-toxic side effects[17,18]. FMD refers to a plantbased, calorie-restricted, low sugar, low protein, and high-fat dietary composition administered cyclically and alternated with refeeding periods sufficient to prevent or minimize lean body mass loss (the caloric content of the FMD that we used for this study is indicated in the “Methods” session)[24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
