FASTING-MIMICKING DIET-BASED NON-TOXIC COMBINATION THERAPY IN CANCER TREATMENT: FROM MOLECULES TO BEDSIDE

Fasting and fasting-mimicking diet (FMD) was shown to delay tumor progression and sensitize a wide range of tumor types to the toxic effect of chemotherapy, through a mechanism which can involve the lowering of IGF-1 and glucose levels. Here, I evaluate FMD-based non-toxic interventions for the treatment of KRAS mutant cancer, focusing on colorectal cancer (CRC). KRAS activating mutations are predictors of poor prognosis and resistance to standard and targeted anti-cancer treatments, making the patient’s survival rate very poor. Recently, a pharmacological dose of vitamin C has been proposed to be effective in the treatment of KRAS mutant colorectal cancer (CRC), however its mechanism of action remains controversial and its efficacy limited. A growing body of evidence indicates that the increased ROS levels and disruption of iron metabolism characterizing tumor cells, are responsible for vitamin C-mediated toxicity. Free labile iron, by reacting with hydrogen peroxide generated through vitamin C oxidation, leads to the formation of hydroxyl radical (Fenton reaction), which causes oxidative damages and cell death. In my thesis, I show that vitamin C alone has a relatively mild toxic effect against CRC and I discovered that this is caused in part by the up-regulation of the stress-inducible protein heme-oxygenase-1 (HO-1). FMD can cause a major enhancement in vitamin C toxicity in KRAS mutant CRC both in vitro and in vivo. The mechanism underlying this effect involves, at least in part, the FMD-dependent downregulation of HO-1. I show that FMD, by reverting the HO-1 induction mediated by vitamin C, is able to reduce ferritin level, leading to an increase in free ferrous ions (Fe2+). The increase of Fe2+, together with a dramatic enhancement of ROS generation, leads to DNA damage and cell death, probably through Fenton reaction. Collectively, my findings show that FMD represents a safe therapeutic intervention, able to potentiate vitamin C anti-cancer effect. In addition, I provide evidence indicating that FMD and vitamin C combo therapy enhances oxaliplatin efficacy in KRAS-driven CRC mouse models, thus representing a promising therapeutic option, which can be hopefully translated into the clinic.