Fasting and cancer: molecular mechanisms and clinical application

Abstract

The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer. Fasting or fasting-mimicking diets (FMDs) lead to wide alterations in growth factors and in metabolite levels, generating environments that can reduce the capability of cancer cells to adapt and survive and thus improving the effects of cancer therapies. In addition, fasting or FMDs increase resistance to chemotherapy in normal but not cancer cells and promote regeneration in normal tissues, which could help prevent detrimental and potentially life-threatening side effects of treatments. While fasting is hardly tolerated by patients, both animal and clinical studies show that cycles of low-calorie FMDs are feasible and overall safe. Several clinical trials evaluating the effect of fasting or FMDs on treatment-emergent adverse events and on efficacy outcomes are ongoing. We propose that the combination of FMDs with chemotherapy, immunotherapy or other treatments represents a potentially promising strategy to increase treatment efficacy, prevent resistance acquisition and reduce side effects.

Fig. 1 ∣. Differential stress resistance versus differential stress sensitization.

Chemotherapy acts on both cancer cells and normal cells, inducing tumour shrinkage but almost inevitably also causing side effects that can be severe or even life threatening because of the damage to many epithelial and non-epithelial tissues. On the basis of the available preclinical data, fasting or a fasting-mimicking diet (FMD) could prove useful to separate the effects of chemotherapy, and possibly of newer cancer drugs, on normal versus cancer cells. Owing to the presence of oncogenic mutations that constitutively activate growth-promoting signalling cascades, cancer cells fail to properly adapt to starvation conditions. As a result, many types of cancer cells, but not normal cells, experience functional imbalances, becoming sensitized to toxic agents, including chemotherapy (differential stress sensitization). Conversely, fasting or an FMD initiates an evolutionarily conserved molecular response that makes normal cells but not cancer cells more resistant to stressors, including chemotherapy (differential stress resistance). The predicted clinical translation of these differential effects of fasting or FMDs on normal versus cancer cells is a reduction in the side effects of cancer treatments, on the one hand, and improved tumour responses, patient progression-free survival and overall survival, on the other.

Fig. 2 ∣. Mechanisms of fasting or FMD-dependent killing of cancer cells in solid tumours.

Preclinical and initial clinical data indicate that fasting or fasting-mimicking diets (FMDs) reduce the levels of tumour growth-promoting nutrients and factors, including glucose, IGF1 and insulin. Fasting can cause an anti-Warburg effect by reducing glucose uptake via glucose transporters (GLUTs) and aerobic glycolysis and forcing cancer cells to increase oxidative phosphorylation (OxPhos); this increases the production of reactive oxygen species (ROS) in cancer cells and, resultantly, oxidative DNA damage, p53 activation, DNA damage and cell death, particularly in response to chemotherapy. By activating autophagy, fasting can reduce CD73 levels in some cancer cells, thereby blunting adenosine production in the extracellular environment and preventing the shift of macrophages towards an immunosuppressive M2 phenotype. Finally, fasting or FMDs can downregulate haem oxygenase 1 (HO1) expression in breast cancer cells, which makes them more susceptible to CD8⁺ cytotoxic T cells, possibly by countering the immunosuppressive effect of regulatory T (T_reg) cells. Notably, fasting or an FMD can have very different and even opposite effects in different cancer cell types or even within the same cancer cell type.

Fig. 3 ∣. Working hypothesis for the effects of the combination of fasting and/or FMDs with standard therapy in oncology.

a ∣ The benefit of cancer treatments is limited by the development of resistance to the agents that are employed but also by treatment-emergent adverse events (TEAEs), which can be severe or even life threatening and may require hospitalization (G3 and/or G4 TEAEs according to Common Terminology Criteria for Adverse Events). Disease progression under treatment and G3 and/or G4 TEAEs are the main causes of treatment discontinuations and of the switch to other lines of treatment or to palliative care. b ∣ Fasting-mimicking diets (FMDs) combined with standard treatments are predicted to increase the ability of the latter to be curative or, at least, to delay the emergence of resistant cancer cell clones. In addition, cycles of fasting or FMDs are anticipated to reduce treatment toxicity, possibly switching G3 and/or G4 TEAEs to less severe G1 and/or G2 TEAEs, and to help patients maintain their quality of life throughout therapy.