Review
Caloric restriction and cancer: molecular mechanisms and clinical implications

https://doi.org/10.1016/j.molmed.2014.05.001Get rights and content

Highlights

  • Caloric restriction (CR) and its mimetics improve lifespan and reduce cancer incidence.

  • CR and CR mimetics sensitize cancer cells to chemotherapy.

  • CR and CR mimetics combined with chemotherapy enhance anticancer immune responses.

Caloric restriction (CR) is currently the most robust environmental intervention known to increase healthy life and prolong lifespan in several models, from yeast to mice. Although the protective effect of CR on the incidence of cancer is well established, its impact on tumor cell responses to chemotherapeutic treatment is currently being investigated. Interestingly, the molecular mechanisms required to extend lifespan upon reduced food intake are being evaluated, and these mechanisms may offer new opportunities for therapeutic intervention. In addition, new findings suggest a beneficial effect of CR in enhancing the efficiency of tumor cell killing by chemotherapeutic drugs and inducing an anticancer immune response.

Section snippets

Link between metabolism and cancer

The link between cell metabolism and cancer at the cellular level has long been known. In the 1950s Otto Warburg observed that cancer cells show sustained aerobic glycolysis, now known as the Warburg effect. Glycolysis can occur normally in hypoxic cells and is inhibited in the presence of oxygen (the Pasteur effect). Metabolic dysregulation can be controlled by the activation of oncogenes or the inhibition of tumor suppressors and is linked to drug resistance of cancer cells [1]. Because the

Molecular effects of caloric restriction

Although the benefits of CR on health and lifespan were first described nearly a century ago 7, 9, there is a renewed interest in CR of late, with an increasing number of reports demonstrating direct connections among dietary practices, cancer outcomes, and obesity. The protective effects of CR on the incidence of cancer has been observed in numerous studies of spontaneous and chemically induced tumors in rodents [7], including long-lived wild mice [10] and scenarios where the CR was initiated

Mimicking caloric restriction using pharmacological agents

Based on the impact of CR on age-related diseases, stress resistance, and cancer, pharmaceutical organizations have focused on the development of CR mimetics to benefit from the advantages of CR without significantly reducing food intake. CR mimetics are defined as molecules leading to one or several physiological changes induced by CR including reduction in blood glucose, insulin, and triglyceride while elevating blood ketone bodies. The three most studied compounds are resveratrol, metformin,

Caloric restriction and chemotherapy

Numerous CR mimetics have been shown to have anticancer properties and are currently being tested in clinical trials to treat solid tumors and lymphomas (Table 1). As observed for CR, epidemiological studies have shown that diabetic patients treated with the CR mimetic metformin have a reduced risk of developing various types of cancer [53]. Metformin efficiently reduces spontaneous tumor growth [53]. This effect could be linked to the ability of this compound to selectively kill CD44high/CD24

Concluding remarks

It has been known for more than 70 years that CR is among the most reliable intervention to prevent age-related disorders and extend lifespan. It is clear that no single pathway accounts for all the anticancer effects of CR. The impact of CR on oncogenesis and the response to chemotherapy is still being elucidated (Box 3). Several hypotheses have been proposed, but firm scientific evidence is still needed. Although the role of fasting on the protection of healthy tissues is suggested, the

Acknowledgments

This work was supported by the Fondation ARC (Association pour la Recherche sur le Cancer), la Fondation de France, the Agence Nationale de la Recherche (ANR-09-JCJC-0003), and the Cancéropole PACA.

Glossary

Adenosine monophosphate-activated protein kinase (AMPK)
a serine–threonine kinase which consists of a heterotrimeric complex composed of the catalytic alpha subunit and two regulatory beta and gamma subunits. AMPK is a regulator of energy homeostasis and is implicated in glucose and lipid metabolism.
Cachexia
a symptom of patients suffering from cancer, consisting of a marked loss of weight and muscle atrophy.
Caloric restriction (CR)
the reduction of caloric intake without the induction of

References (96)

  • A. Csibi

    The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4

    Cell

    (2013)
  • K.J. Pearson

    Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span

    Cell Metab.

    (2008)
  • S. Timmers

    Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans

    Cell Metab.

    (2011)
  • S.J. Park

    Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

    Cell

    (2012)
  • N.L. Price

    SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function

    Cell Metab.

    (2012)
  • Y. Sancak

    Ragulator–Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids

    Cell

    (2010)
  • Y. Fang

    Duration of rapamycin treatment has differential effects on metabolism in mice

    Cell Metab.

    (2013)
  • I. Bjedov

    Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster

    Cell Metab.

    (2010)
  • S.M. Blättler

    Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling

    Cell Metab.

    (2012)
  • D.B. Shackelford

    LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin

    Cancer Cell

    (2013)
  • F. Vaillant

    Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer

    Cancer Cell

    (2013)
  • K. Chen

    Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms

    J. Biol. Chem.

    (2011)
  • R.L. Veech

    The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism

    Prostaglandins Leukot. Essent. Fatty Acids

    (2004)
  • R. Wang

    The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation

    Immunity

    (2011)
  • R.R. Rao

    Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8+ T cell differentiation

    Immunity

    (2012)
  • X. Tai

    Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals

    Immunity

    (2013)
  • O. Meynet

    Caloric restriction modulates Mcl-1 expression and sensitizes lymphomas to BH3 mimetic in mice

    Blood

    (2013)
  • V.D. Longo et al.

    Fasting: molecular mechanisms and clinical applications

    Cell Metab.

    (2014)
  • Y. Li

    Epigenetic regulation of caloric restriction in aging

    BMC Med.

    (2011)
  • A.J. Papoutsis

    Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells

    J. Nutr.

    (2010)
  • C. Muñoz-Pinedo

    Cancer metabolism: current perspectives and future directions

    Cell Death Dis.

    (2012)
  • M.J. Khandekar

    Molecular mechanisms of cancer development in obesity

    Nat. Rev. Cancer

    (2011)
  • C.M. Kitahara

    Prospective investigation of body mass index, colorectal adenoma, and colorectal cancer in the prostate, lung, colorectal, and ovarian cancer screening trial

    J. Clin. Oncol.

    (2013)
  • C. Yuan

    Prediagnostic body mass index and pancreatic cancer survival

    J. Clin. Oncol.

    (2013)
  • D.C. Willcox

    The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load

    J. Am. Coll. Nutr.

    (2009)
  • K.B. Michels et al.

    Caloric restriction and incidence of breast cancer

    JAMA

    (2004)
  • A. Tannenbaum

    The genesis and growth of tumors. II. Effects of caloric restriction per se

    Cancer Res.

    (1942)
  • R. Weindruch et al.

    Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence

    Science

    (1982)
  • J.M. Harper

    Does caloric restriction extend life in wild mice?

    Aging Cell

    (2006)
  • J.M. Dhahbi

    Temporal linkage between the phenotypic and genomic responses to caloric restriction

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • R.J. Colman

    Caloric restriction delays disease onset and mortality in rhesus monkeys

    Science

    (2009)
  • J.A. Mattison

    Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study

    Nature

    (2012)
  • P. Mukherjee

    Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors

    Clin. Cancer Res.

    (2004)
  • J. Marsh

    Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma

    Clin. Cancer Res.

    (2008)
  • T.J. Mulrooney

    Influence of caloric restriction on constitutive expression of NF-κB in an experimental mouse astrocytoma

    PLoS ONE

    (2011)
  • S.D. Hursting

    Calorie restriction and cancer prevention: a mechanistic perspective

    Cancer Metab.

    (2013)
  • E.J. Gallagher et al.

    Minireview: IGF, insulin, and cancer

    Endocrinology

    (2011)
  • A.J. Price

    Insulin-like growth factor-I concentration and risk of prostate cancer: results from the European Prospective Investigation into Cancer and Nutrition

    Cancer Epidemiol. Biomarkers Prev.

    (2012)
  • Cited by (93)

    • Cancer

      2023, Ketogenic: The Science of Therapeutic Carbohydrate Restriction in Human Health
    View all citing articles on Scopus
    View full text