Dietary restrictions, including fasting (or long-term starvation), calorie restriction (CR), and short-term starvation (STS), are considered a strong rationale that may protect against various diseases, including age-related diseases and cancer. Among dietary approaches, STS, in which food is not consumed during designed fasting periods but is typically not restricted during designated feeding periods, seems to be more suitable, because other dietary regimens involving prolonged fasting periods could worsen the health conditions of cancer patients, being they already naturally prone to weight loss. Until now, the limited amount of available data does not point to a single gene, pathway, or molecular mechanism underlying the benefits to the different dietary approaches. It is well known that the healthy effect is mediated in part by the reduction of nutrient-related pathways. The calorie restriction and starvation (long- and short-term) also suppress the inflammatory response reducing the expression, for example, of IL-10 and TNF-α, mitigating pro-inflammatory gene expression and increasing anti-inflammatory gene expression. The dietary restriction may regulate both genes involved in cellular proliferation and factors associated to apoptosis in normal and cancer cells. Finally, dietary restriction is an important tool that may influence the response to chemotherapy in preclinical models. However, further data are needed to correlate dietary approaches with chemotherapeutic treatments in human models. The aim of this review is to discuss the effects of various dietary approaches on the cancer progression and therapy response, mainly in preclinical models, describing some signaling pathways involved in these processes.
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Codeluppi S, Gregory EN, Kjell J, Wigerblad G, Olson L, Svensson CI. Influence of rat substrain and growth conditions on the characteristics of primary cultures of adult rat spinal cord astrocytes. J Neurosci Methods. 2011;197(1):118–27.
Pontarin G, Ferraro P, Rampazzo C, Kollberg G, Holme E, Reichard P, et al. Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase. J Biol Chem. 2011;286(13):11132–40.
Pirkmajer S, Chibalin AV. Serum starvation: caveat emptor. Am J Physiol Cell Physiol. 2011;301(2):C272–9.
Arrington DD, Schnellmann RG. Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress. Am J Physiol Cell Physiol. 2008;294(2):C641–50.
Bhutia SK, Kegelman TP, Das SK, Azab B, Su ZZ, Lee SG, et al. Astrocyte elevated gene-1 induces protective autophagy. Proc Natl Acad Sci U S A. 2010;107(51):22243–8.
Terra LF, Garay-Malpartida MH, Wailemann RA, Sogayar MC, Labriola L. Recombinant human prolactin promotes human beta cell survival via inhibition of extrinsic and intrinsic apoptosis pathways. Diabetologia. 2011;54(6):1388–97.
Liu HS, Hsu PY, Lai MD, Chang HY, Ho CL, Cheng HL, et al. An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells. Carcinogenesis. 2010;31(8):1456–64.
Bousette N, Chugh S, Fong V, Isserlin R, Kim KH, Volchuk A, et al. Constitutively active calcineurin induces cardiac endoplasmic reticulum stress and protects against apoptosis that is mediated by alpha-crystallin-B. Proc Natl Acad Sci U S A. 2010;107(43):18481–6.
Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 2011;585(11):1537–42.
Brandhorst S, Wei M, Hwang S, Morgan TE, Longo VD. Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression. Exp Gerontol. 2013;48(10):1120–8.
Anton S, Leeuwenburgh C. Fasting or caloric restriction for healthy aging. Exp Gerontol. 2013;48(10):1003–5.
Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986;116(4):641–54.
Lefevre M, Redman LM, Heilbronn LK, Smith JV, Martin CK, Rood JC, et al. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis. 2009;203(1):206–13.
Larson-Meyer DE, Heilbronn LK, Redman LM, Newcomer BR, Frisard MI, Anton S, et al. Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care. 2006;29(6):1337–44.
Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007;4(3), e76.
Aris JP, Alvers AL, Ferraiuolo RA, Fishwick LK, Hanvivatpong A, Hu D, et al. Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast. Exp Gerontol. 2013;48(10):1107–19.
Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E. Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ Res. 2012;110(8):1125–38.
Hofer T, Fontana L, Anton SD, Weiss EP, Villareal D, Malayappan B, et al. Long-term effects of caloric restriction or exercise on DNA and RNA oxidation levels in white blood cells and urine in humans. Rejuvenation Res. 2008;11(4):793–9.
Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012;4(124):124ra127.
Robertson LT, Mitchell JR. Benefits of short-term dietary restriction in mammals. Exp Gerontol. 2013;48(10):1043–8.
Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011;30(30):3305–16.
Lee GY, Lee JJ, Lee SM. Antioxidant and anticoagulant status were improved by personalized dietary intervention based on biochemical and clinical parameters in cancer patients. Nutr Cancer. 2015;67(7):1083–92.
Davis LM, Pauly JR, Readnower RD, Rho JM, Sullivan PG. Fasting is neuroprotective following traumatic brain injury. J Neurosci Res. 2008;86(8):1812–22.
Fontana L, Partridge L, Longo VD. Extending healthy life span—from yeast to humans. Science. 2010;328(5976):321–6.
Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003;421(6919):182–7.
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13.
Kim DH, Kim JY, Yu BP, Chung HY. The activation of NF-kappaB through Akt-induced FOXO1 phosphorylation during aging and its modulation by calorie restriction. Biogerontology. 2008;9(1):33–47.
Partridge L, Bruning JC. Forkhead transcription factors and ageing. Oncogene. 2008;27(16):2351–63.
Ramsey MM, Ingram RL, Cashion AB, Ng AH, Cline JM, Parlow AF, et al. Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. Endocrinology. 2002;143(10):4139–42.
Prisco M, Romano G, Peruzzi F, Valentinis B, Baserga R. Insulin and IGF-I receptors signaling in protection from apoptosis. Horm Metab Res. 1999;31(2-3):80–9.
Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA. Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab. 2005;289(1):E23–9.
Brown-Borg HM, Rakoczy SG. Catalase expression in delayed and premature aging mouse models. Exp Gerontol. 2000;35(2):199–212.
van den Bosch HM, Bunger M, de Groot PJ, van der Meijde J, Hooiveld GJ, Muller M. Gene expression of transporters and phase I/II metabolic enzymes in murine small intestine during fasting. BMC Genomics. 2007;8:267.
Chiba T, Ezaki O. Dietary restriction suppresses inflammation and delays the onset of stroke in stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun. 2010;399(1):98–103.
Lee C, Raffaghello L, Longo VD. Starvation, detoxification, and multidrug resistance in cancer therapy. Drug Resist Updat. 2012;15(1-2):114–22.
Longo VD, Lieber MR, Vijg J. Turning anti-ageing genes against cancer. Nat Rev Mol Cell Biol. 2008;9(11):903–10.
Shi Y, Felley-Bosco E, Marti TM, Orlowski K, Pruschy M, Stahel RA. Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin. BMC Cancer. 2012;12:571.
Dong S, Khoo A, Wei J, Bowser RK, Weathington NM, Xiao S, et al. Serum starvation regulates E-cadherin upregulation via activation of c-Src in non-small-cell lung cancer A549 cells. Am J Physiol Cell Physiol. 2014;307(9):C893–9.
Wong AS, Gumbiner BM. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol. 2003;161(6):1191–203.
Braun F, Bertin-Ciftci J, Gallouet AS, Millour J, Juin P. Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-x(L) inhibition. PLoS One. 2011;6(8), e23577.
Lu C, Shi Y, Wang Z, Song Z, Zhu M, Cai Q, et al. Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway. FEBS Lett. 2008;582(18):2703–8.
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27–42.
Rodriguez-Vargas JM, Ruiz-Magana MJ, Ruiz-Ruiz C, Majuelos-Melguizo J, Peralta-Leal A, Rodriguez MI, et al. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res. 2012;22(7):1181–98.
Formentini L, Macchiarulo A, Cipriani G, Camaioni E, Rapizzi E, Pellicciari R, et al. Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure. J Biol Chem. 2009;284(26):17668–76.
Siggens L, Figg N, Bennett M, Foo R. Nutrient deprivation regulates DNA damage repair in cardiomyocytes via loss of the base-excision repair enzyme OGG1. FASEB J. 2012;26(5):2117–24.
Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science. 2008;319(5868):1352–5.
Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991;51(3):794–8.
Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
Medema RH, Bos JL. The role of p21ras in receptor tyrosine kinase signaling. Crit Rev Oncog. 1993;4(6):615–61.
Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87(2):159–70.
Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors. Endocr Rev. 1994;15(1):80–101.
Flemstrom G, Bengtsson MW, Makela K, Herzig KH. Effects of short-term food deprivation on orexin-A-induced intestinal bicarbonate secretion in comparison with related secretagogues. Acta Physiol (Oxford). 2010;198(3):373–80.
Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008;105(24):8215–20.
Russo A, Rizzo S. Could starvation minimize chemotherapy-induced toxicities? Expert Opin Ther Targets. 2008;12(9):1205–7.
Dirks-Naylor AJ, Kouzi SA, Yang S, Tran NT, Bero JD, Mabolo R, et al. Can short-term fasting protect against doxorubicin-induced cardiotoxicity? World J Biol Chem. 2014;5(3):269–74.
Laconi E, Tessitore L, Milia G, Yusuf A, Sarma DS, Todde P, et al. The enhancing effect of fasting/refeeding on the growth of nodules selectable by the resistant hepatocyte model in rat liver. Carcinogenesis. 1995;16(8):1865–9.
Premoselli F, Sesca E, Binasco V, Caderni G, Tessitore L. Fasting/re-feeding before initiation enhances the growth of aberrant crypt foci induced by azoxymethane in rat colon and rectum. Int J Cancer. 1998;77(2):286–94.
Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4(8):579–91.
Toren P, Mora BC, Venkateswaran V. Diet, obesity, and cancer progression: are adipocytes the link? Lipid Insights. 2013;6:37–45.
Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71(7):2455–65.
Berstein LM, Kovalevskij AY, Poroshina TE, Kotov AV, Kovalenko IG, Tsyrlina EV, et al. Signs of proinflammatory/genotoxic switch (adipogenotoxicosis) in mammary fat of breast cancer patients: role of menopausal status, estrogens and hyperglycemia. Int J Cancer. 2007;121(3):514–9.
Wang YY, Lehuede C, Laurent V, Dirat B, Dauvillier S, Bochet L, et al. Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Cancer Lett. 2012;324(2):142–51.
Sacca PA, Creydt VP, Choi H, Mazza ON, Fletcher SJ, Vallone VB, et al. Human periprostatic adipose tissue: its influence on prostate cancer cells. Cell Physiol Biochem. 2012;30(1):113–22.
Ribeiro R, Monteiro C, Catalan V, Hu P, Cunha V, Rodriguez A, et al. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue. BMC Med. 2012;10:108.
Park J, Scherer PE. Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest. 2012;122(11):4243–56.
Hermsdorff HH, Zulet MA, Abete I, Martinez JA. Discriminated benefits of a Mediterranean dietary pattern within a hypocaloric diet program on plasma RBP4 concentrations and other inflammatory markers in obese subjects. Endocrine. 2009;36(3):445–51.
Champ CE, Baserga R, Mishra MV, Jin L, Sotgia F, Lisanti MP, et al. Nutrient restriction and radiation therapy for cancer treatment: when less is more. Oncologist. 2013;18(1):97–103.
Seyfried TN, Flores R, Poff AM, D’Agostino DP, Mukherjee P. Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett. 2015;356(2 Pt A):289–300.
Fanale D, Bazan V, Corsini LR, Caruso S, Insalaco L, Castiglia M, et al. HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions. Breast Cancer Res Treat. 2013;140(3):505–17.
Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, et al. Fasting and cancer treatment in humans: a case series report. Aging (Albany NY). 2009;1(12):988–1007.
Fanale D, Bazan V, Caruso S, Castiglia M, Bronte G, Rolfo C, et al. Hypoxia and human genome stability: downregulation of BRCA2 expression in breast cancer cell lines. Biomed Res Int. 2013;2013:746858.
Shim HS, Wei M, Brandhorst S, Longo VD. Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells. Cancer Res. 2015;75(6):1056–67.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
Shin JS, Hong SW, Lee SL, Kim TH, Park IC, An SK, et al. Serum starvation induces G1 arrest through suppression of Skp2-CDK2 and CDK4 in SK-OV-3 cells. Int J Oncol. 2008;32(2):435–9.
Kannen V, Zanette DL, Fernandes CR, Ferreira FR, Marini T, Carvalho MC, et al. High-fat diet causes an imbalance in the colonic serotonergic system promoting adipose tissue enlargement and dysplasia in rats. Toxicol Lett. 2012;213(2):135–41.
Garcia SB, Barros LT, Turatti A, Martinello F, Modiano P, Ribeiro-Silva A, et al. The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen. Cancer Lett. 2006;240(2):221–4.
Simsek T, Canturk NZ, Canturk Z, Yirmibesoglu OA, Bayhan Z, Oz S. Evaluation of relationship between serum lipids levels with colorectal carcinoma: a single center prospective case control study. Hepatogastroenterology. 2014;61(129):59–64.
Kaska M, Grosmanova T, Havel E, Hyspler R, Petrova Z, Brtko M, et al. The impact and safety of preoperative oral or intravenous carbohydrate administration versus fasting in colorectal surgery—a randomized controlled trial. Wien Klin Wochenschr. 2010;122(1-2):23–30.
Yang CS, Newmark HL. The role of micronutrient deficiency in carcinogenesis. Crit Rev Oncol Hematol. 1987;7(4):267–87.
Kannen V, Fernandes CR, Stopper H, Zanette DL, Ferreira FR, Frajacomo FT, et al. Colon preneoplasia after carcinogen exposure is enhanced and colonic serotonergic system is suppressed by food deprivation. Toxicology. 2013;312:123–31.
Rolfo C, Fanale D, Hong DS, Tsimberidou AM, Piha-Paul SA, Pauwels P, et al. Impact of microRNAs in resistance to chemotherapy and novel targeted agents in non-small cell lung cancer. Curr Pharm Biotechnol. 2014;15(5):475–85.
Katsuya Y, Fujiwara Y, Sunami K, Utsumi H, Goto Y, Kanda S, et al. Comparison of the pharmacokinetics of erlotinib administered in complete fasting and 2 h after a meal in patients with lung cancer. Cancer Chemother Pharmacol. 2015;76(1):125–32.
Aronson WJ, Barnard RJ, Freedland SJ, Henning S, Elashoff D, Jardack PM, et al. Growth inhibitory effect of low fat diet on prostate cancer cells: results of a prospective, randomized dietary intervention trial in men with prostate cancer. J Urol. 2010;183(1):345–50.
Li X, Lao Y, Zhang H, Wang X, Tan H, Lin Z, et al. The natural compound Guttiferone F sensitizes prostate cancer to starvation induced apoptosis via calcium and JNK elevation. BMC Cancer. 2015;15:254.
Bonorden MJ, Rogozina OP, Kluczny CM, Grossmann ME, Grande JP, Lokshin A, et al. Cross-sectional analysis of intermittent versus chronic caloric restriction in the TRAMP mouse. Prostate. 2009;69(3):317–26.
Conflicts of interest
Antonina Cangemi, Daniele Fanale and Gaetana Rinaldi contributed equally to this work.
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Cangemi, A., Fanale, D., Rinaldi, G. et al. Dietary restriction: could it be considered as speed bump on tumor progression road?. Tumor Biol. 37, 7109–7118 (2016). https://doi.org/10.1007/s13277-016-5044-8