Fasting and cancer: molecular mechanisms and clinical application

Alessio Nencioni, Irene Caffa, Salvatore Cortellino and Valter D. Longo
Nature Reviews – Cancer volume 18, November 2018

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.

Starvation, Stress Resistance, and Cancer

Roberta Buono and Valter D. Longo, Trends in Endocrinology & Metabolism, April 2018, Vol. 29, No. 4

Cancer cells are characterized by dysregulation in signal transduction and metabolic pathways leading to increased glucose uptake, altered mitochon-drial function, and the evasion of antigrowth signals.

Fasting and fasting-mimicking diets (FMDs) provide a particularly promising intervention to pro-mote differential effects in normal and malignant cells.

These effects are caused in part by the reduction in IGF-1, insulin, and glucose and the increase in IGFBP1 and ketone bodies, which generate conditions that force cancer cells to rely more on metabolites and factors that are limited in the blood, thus resulting in cell death.

Here we discuss the cellular and animal experiments demonstrating the differential effects of fasting on normal and cancer cells and the mechanisms responsible for these effects.

Periodic fasting starves cisplatin-resistant cancers to death

Novella Guidi & Valter D Longo, The EMBO Journal 37:e99815 | 2018

Treatment of cancers with the cytotoxic agent cisplatin frequently evokes resis-tance, accompanied by rewiring of meta-bolic pathways, limiting its clinical use.

Recent research by Obrist et al (2018) shows that cisplatin-resistant growth of lung adenocarcinoma is particularly vulnerable to periodic fasting cycles and starvation-induced cell death, due to its dependency on glutamine, required for nucleoside biosynthesis, suggesting an opportunity for nutritional anti-cancer interventions.

PNAS March 8, 2008

Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy

PNAS August 17, 2008

PNAS – Starvation Enhances Chemotherapy

Science Magazine August 29, 2008

Fasting Can Blunt Chemotherapy’s Debilitating Side Effects?

Cancer Research February 15, 2010

Cancer Research – Selectively Protect Normal Cells by Reducing IGF-1

Landes Bioscience February 2, 2011

Fasting and differential chemotherapy protection in patients.

NPG July 28, 2011

Fasting vs. dietary restriction in cellular protection and cancer treatment: from model organisms to patients.