Trends in Molecular Medicine
ReviewCaloric restriction and cancer: molecular mechanisms and clinical implications
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
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