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OPINION

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.

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Fig. 1: Differential stress resistance versus differential stress sensitization.
Fig. 2: Mechanisms of fasting or FMD-dependent killing of cancer cells in solid tumours.
Fig. 3: Working hypothesis for the effects of the combination of fasting and/or FMDs with standard therapy in oncology.

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Acknowledgements

This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG#17736 to A.N. and IG#17605 to V.D.L.), the Seventh Framework Program ATHERO-B-CELL (#602114 to A.N.), the Fondazione Umberto Veronesi (to A.N. and V.D.L.), the Italian Ministry of Health (GR-2011-02347192 to A.N.), the 5 × 1000 2014 Funds to the Istituto di Ricovero e Cura a Carattere Scientifico per l’Oncologia (IRCCS) Ospedale Policlinico San Martino (to A.N.), the BC161452 and BC161452P1 grants of the Breast Cancer Research Program (US Department of Defense) (to V.D.L. and to A.N., respectively) and the US National Institute on Aging–National Institutes of Health (NIA–NIH) grants AG034906 and AG20642 (to V.D.L.).

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Nature Reviews Cancer thanks O. Yilmaz, C. C. Zhang and the anonymous reviewer for their contribution to the peer review of this work.

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V.D.L. substantially contributed to discussion of content, wrote the manuscript and reviewed and/or edited it before submission. A.N. researched data for the manuscript, substantially contributed to discussion of content and wrote the manuscript. I.C. and S.C. researched data for the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to Valter D. Longo.

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A.N. and I.C. are inventors on three patents of methods for treating cancer by fasting-mimicking diets that are currently under negotiation with L-Nutra Inc. V.D.L. is the founder of L-Nutra Inc.

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Nencioni, A., Caffa, I., Cortellino, S. et al. Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer 18, 707–719 (2018). https://doi.org/10.1038/s41568-018-0061-0

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