Purpose of Review
Fasting can be defined as stress on the cell due to nutrient deprivation which modulates metabolic regulation and influences several gene expressions. During fasting, nutrient (majorly glucose) limitation forces different organs to shift their energy sources. Ketosis starts at a faster rate in absence of glucose. The cancer cells have higher dependence on glucose for their fast cell division rate. Fasting limits the adaptability of the cancer cells and increases the therapeutic efficacy of the chemotherapeutics. The main purpose of this review is to focus on the clinical result and plausible mechanism of fasting or caloric restriction on the prevention, suppression, treatment of cancer, and chemotherapy-induced toxicity reduction.
Fasting has been implicated as it promotes autophagy and plays a key role as tumor inhibitory action during fasting. In addition, transcription factor p53 also gets upregulated during fasting and regulates pro-apoptotic function in tumor cells. Also, p53 transactivates different genes for ketogenesis process. Earlier reports have suggested that prolonged fasting in some of the cancer patients is considered to be safe and more capable of minimizing chemotherapy-mediated tumor growth and toxicity.
Fasting has established a critical link between minimal level of glucose and elevated ketosis, thereby possess challenging environment for cancer cell survival. Cross talk between p53 gene and ketosis shows considerable episodes of energy metabolism pathway and upregulates the tumor suppression. The level of glucose drops during fasting stage which sensitizes the cancer cells due to energy deprivation and increases the efficacy of chemotherapeutic agents.
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Phosphotidyl inositol 3 kinase
Protein kinase B
Mammalian target of rapamycin
Hypoxia-inducible factor 1α
Mitochondrial fission protein 1
Dynamin-related protein 1
AMP-activated protein kinase
Phosphatase and tensin homolog
DNA repair protein
DNA damage–inducible transcript 4
Cyclin-dependent kinase inhibitor 1a
- Sesn-1 and 2:
Sestrin 1 and 2
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of majorimportance
Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR, et al. Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial. J Clin Oncol. 2012;30(19):2314–26. https://doi.org/10.1200/JCO.2011.37.9792.
Reilly JJ, Kelly J. Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review. Int J Obes (Lond). 2011;35(7):891–8. https://doi.org/10.1038/ijo.2010.222.
Thomson CA, Stopeck AT, Bea JW, Cussler E, Nardi E, Frey G, et al. Changes in body weight and metabolic indexes in overweight breast cancer survivors enrolled in a randomized trial of low-fat vs. reduced carbohydrate diets. Nutr Cancer. 2010;62(8):1142–52. https://doi.org/10.1080/01635581.2010.513803.
Yang P, Zhou Y, Chen B, Wan HW, Jia GQ, Bai HL, et al. Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur J Cancer. 2009;45(16):2867–73. https://doi.org/10.1016/j.ejca.2009.04.019.
Ligibel JA, Strickler HD. Obesity and its impact on breast cancer: tumor incidence, recurrence, survival, and possible interventions. Am Soc Clin Oncol Educ Book. 2013:52–9. https://doi.org/10.1200/EdBook_AM.2013.33.52https://doi.org/10.14694/EdBook_AM.2013.33.52
Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002;3(9):565–74. https://doi.org/10.1016/s1470-2045(02)00849-5.
Garfinkel L. Overweight and cancer. Ann Intern Med. 1985;103(6_Part_2):1034–6. https://doi.org/10.7326/0003-4819-103-6-1034.
Murphy N, Moreno V, Hughes DJ, Vodicka L, Vodicka P, Aglago EK, et al. Lifestyle and dietary environmental factors in colorectal cancer susceptibility. Mol Aspects Med. 2019;69:2–9. https://doi.org/10.1016/j.mam.2019.06.005.
Brandhorst S, Longo VD. Fasting and caloric restriction in cancer prevention and treatment. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 2016;207:241–66. https://doi.org/10.1007/978-3-319-42118-6_12. It covers the possible effect of fasting and chemoprevention.
Cifu G, Arem H. Adherence to lifestyle-related cancer prevention guidelines and breast cancer incidence and mortality. Ann Epidemiol. 2018;28(11):767-73 e1. https://doi.org/10.1016/j.annepidem.2018.09.002.
Nencioni A, Caffa I, Cortellino S, Longo VD. Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer. 2018;18(11):707–19. https://doi.org/10.1038/s41568-018-0061-0.
Zhang J, Deng Y, Khoo BL. Fasting to enhance cancer treatment in models: the next steps. J Biomed Sci. 2020;27(1):58. https://doi.org/10.1186/s12929-020-00651-0.
Tan-Shalaby J. Ketogenic diets and cancer: emerging evidence. Federal practitioner : for the health care professionals of the VA, DoD, and PHS. 2017;34(Suppl 1):37S-42S.
Smyl C. Ketogenic Diet and Cancer-a Perspective. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 2016;207:233–40. https://doi.org/10.1007/978-3-319-42118-6_11.
Branco AF, Ferreira A, Simoes RF, Magalhaes-Novais S, Zehowski C, Cope E, et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Invest. 2016;46(3):285–98. https://doi.org/10.1111/eci.12591.
Lv M, Zhu X, Wang H, Wang F, Guan W. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. PLoS ONE. 2014;9(12): e115147. https://doi.org/10.1371/journal.pone.0115147.
Guo JY, White E. Autophagy, Metabolism, and Cancer. Cold Spring Harb Symp Quant Biol. 2016;81:73–8. https://doi.org/10.1101/sqb.2016.81.030981. This article has reported the connection between mechanism of autophagy and its role in cancer.
Deretic V. Autophagosome and phagosome. Methods Mol Biol. 2008;445:1–10. https://doi.org/10.1007/978-1-59745-157-4_1.
Buono R, Longo VD. Starvation, stress resistance, and cancer. Trends Endocrinol Metab. 2018;29(4):271–80. https://doi.org/10.1016/j.tem.2018.01.008. This article has great importance to study the relationship between stages of fasting and its role in the different stages of cancer.
Antunes F, Erustes AG, Costa AJ, Nascimento AC, Bincoletto C, Ureshino RP, et al. Autophagy and intermittent fasting: the connection for cancer therapy? Clinics. 2018;73(suppl 1):e814s. https://doi.org/10.6061/clinics/2018/e814s. This article explains the promising role of intermittent fasting in cancer therapy.
Berrigan D, Perkins SN, Haines DC, Hursting SD. Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis. 2002;23(5):817–22. https://doi.org/10.1093/carcin/23.5.817.
Ma D, Chen X, Zhang PY, Zhang H, Wei LJ, Hu S, et al. Upregulation of the ALDOA/DNA-PK/p53 pathway by dietary restriction suppresses tumor growth. Oncogene. 2018;37(8):1041–8. https://doi.org/10.1038/onc.2017.398.
Schupp M, Chen F, Briggs ER, Rao S, Pelzmann HJ, Pessentheiner AR, et al. Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues. BMC Genomics. 2013;14:758. https://doi.org/10.1186/1471-2164-14-758. The article suggests the probable role of p53 on fasting stages.
Prokesch A, Graef FA, Madl T, Kahlhofer J, Heidenreich S, Schumann A, et al. Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2017;31(2):732–42. https://doi.org/10.1096/fj.201600845R.
Byun S, Seok S, Kim YC, Zhang Y, Yau P, Iwamori N, et al. Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase. Nat Commun. 2020;11(1):807. https://doi.org/10.1038/s41467-020-14384-z.
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. Science translational medicine. 2012;4(124):124ra27. https://doi.org/10.1126/scitranslmed.3003293.
Bauersfeld SP, Kessler CS, Wischnewsky M, Jaensch A, Steckhan N, Stange R, et al. The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study. BMC Cancer. 2018;18(1):476. https://doi.org/10.1186/s12885-018-4353-2.
Di Biase S, Shim HS, Kim KH, Vinciguerra M, Rappa F, Wei M, et al. Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy. PLoS Biol. 2017;15(3): e2001951. https://doi.org/10.1371/journal.pbio.2001951. This article discusses the probable role of fasting on cancer patients undergoing chemotherapy.
Wang L, Shang Z, Zhou Y, Hu X, Chen Y, Fan Y, et al. Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival. Cell Death Dis. 2018;9(2):213. https://doi.org/10.1038/s41419-017-0242-x.
Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41(3):211–8. https://doi.org/10.1016/j.tibs.2015.12.001.
Hsu CC, Tseng LM, Lee HC. Role of mitochondrial dysfunction in cancer progression. Exp Biol Med. 2016;241(12):1281–95. https://doi.org/10.1177/1535370216641787.
Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L, Panzarini E, et al. Lifestyle, oxidative stress, and antioxidants: back and forth in the pathophysiology of chronic diseases. Front Physiol. 2020;11:694. https://doi.org/10.3389/fphys.2020.00694.
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biol Med. 2010;49(11):1603–16. https://doi.org/10.1016/j.freeradbiomed.2010.09.006.
Peake J, Suzuki K. Neutrophil activation, antioxidant supplements and exercise-induced oxidative stress. Exerc Immunol Rev. 2004;10:129–41.
Bi Y, Lei X, Chai N, Linghu E. NOX4: a potential therapeutic target for pancreatic cancer and its mechanism. J Transl Med. 2021;19(1):515. https://doi.org/10.1186/s12967-021-03182-w.
Han M, Zhang T, Yang L, Wang Z, Ruan J, Chang X. Association between NADPH oxidase (NOX) and lung cancer: a systematic review and meta-analysis. J Thorac Dis. 2016;8(7):1704–11. https://doi.org/10.21037/jtd.2016.06.31.
Aseervatham J. Cytoskeletal remodeling in cancer. Biology. 2020;9(11). https://doi.org/10.3390/biology9110385.
Liou GY, Storz P. Reactive oxygen species in cancer. Free Radical Res. 2010;44(5):479–96. https://doi.org/10.3109/10715761003667554.
Mori K, Uchida T, Yoshie T, Mizote Y, Ishikawa F, Katsuyama M, et al. A mitochondrial ROS pathway controls matrix metalloproteinase 9 levels and invasive properties in RAS-activated cancer cells. FEBS J. 2019;286(3):459–78. https://doi.org/10.1111/febs.14671.
Lee SY, Ju MK, Jeon HM, Lee YJ, Kim CH, Park HG, et al. Reactive oxygen species induce epithelialmesenchymal transition, glycolytic switch, and mitochondrial repression through the Dlx2/Snail signaling pathways in MCF7 cells. Mol Med Rep. 2019;20(3):2339–46. https://doi.org/10.3892/mmr.2019.10466.
Sharsher S, Ahmed A, Metwally M, Arisha A, Ahmed K. Intermittent fasting decreases oxidative stress parameters and increases total antioxidant capacity. Biointerface Research in Applied Chemistry. 2022;12:6763–75. https://doi.org/10.33263/BRIAC125.67636775.
Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181–92. https://doi.org/10.1016/j.cmet.2013.12.008.
Savencu CE, Linta A, Farcas G, Bina AM, Cretu OM, Malita DC, et al. Impact of dietary restriction regimens on mitochondria, heart, and endothelial function: a brief overview. Front Physiol. 2021;12: 768383. https://doi.org/10.3389/fphys.2021.768383.
Khraiwesh H, Lopez-Dominguez JA, Lopez-Lluch G, Navas P, de Cabo R, Ramsey JJ, et al. Alterations of ultrastructural and fission/fusion markers in hepatocyte mitochondria from mice following calorie restriction with different dietary fats. J Gerontol A Biol Sci Med Sci. 2013;68(9):1023–34. https://doi.org/10.1093/gerona/glt006.
Kobara M, Furumori-Yukiya A, Kitamura M, Matsumura M, Ohigashi M, Toba H, et al. Short-term caloric restriction suppresses cardiac oxidative stress and hypertrophy caused by chronic pressure overload. J Cardiac Fail. 2015;21(8):656–66. https://doi.org/10.1016/j.cardfail.2015.04.016.
Iffiu-Soltesz Z, Prevot D, Carpene C. Influence of prolonged fasting on monoamine oxidase and semicarbazide-sensitive amine oxidase activities in rat white adipose tissue. J Physiol Biochem. 2009;65(1):11–23. https://doi.org/10.1007/BF03165965.
Gross DN, van den Heuvel AP, Birnbaum MJ. The role of FoxO in the regulation of metabolism. Oncogene. 2008;27(16):2320–36. https://doi.org/10.1038/onc.2008.25.
Yamada E, Singh R. Mapping autophagy on to your metabolic radar. Diabetes. 2012;61(2):272–80. https://doi.org/10.2337/db11-1199.
Bagherniya M, Butler AE, Barreto GE, Sahebkar A. The effect of fasting or calorie restriction on autophagy induction: a review of the literature. Ageing Res Rev. 2018;47:183–97. https://doi.org/10.1016/j.arr.2018.08.004.
Maes H, Rubio N, Garg AD, Agostinis P. Autophagy: shaping the tumor microenvironment and therapeutic response. Trends Mol Med. 2013;19(7):428–46. https://doi.org/10.1016/j.molmed.2013.04.005.
van Niekerk G, Hattingh SM, Engelbrecht AM. Enhanced therapeutic efficacy in cancer patients by short-term fasting: the autophagy connection. Front Oncol. 2016;6:242. https://doi.org/10.3389/fonc.2016.00242. The article has discussed the mechanistic action of fasting in autophagy mediated cancer machinery.
Zhao YG, Zhang H. Core autophagy genes and human diseases. Curr Opin Cell Biol. 2019;61:117–25. https://doi.org/10.1016/j.ceb.2019.08.003.
Goldstein I, Hager GL. Transcriptional and chromatin regulation during fasting - the genomic era. Trends Endocrinol Metab. 2015;26(12):699–710. https://doi.org/10.1016/j.tem.2015.09.005.
Safdie F, Brandhorst S, Wei M, Wang W, Lee C, Hwang S, et al. Fasting enhances the response of glioma to chemo- and radiotherapy. PLoS ONE. 2012;7(9): e44603. https://doi.org/10.1371/journal.pone.0044603.
Saleh AD, Simone BA, Palazzo J, Savage JE, Sano Y, Dan T, et al. Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle. 2013;12(12):1955–63. https://doi.org/10.4161/cc.25016.
Goldhamer AC, Klaper M, Foorohar A, Myers TR. Water-only fasting and an exclusively plant foods diet in the management of stage IIIa, low-grade follicular lymphoma. BMJ case reports. 2015;2015. https://doi.org/10.1136/bcr-2015-211582.
Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Can Res. 2010;70(4):1564–72. https://doi.org/10.1158/0008-5472.CAN-09-3228.
Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell. 2016;30(1):147–60. https://doi.org/10.1016/j.ccell.2016.05.016.
Sun P, Wang H, He Z, Chen X, Wu Q, Chen W, et al. Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages. Oncotarget. 2017;8(43):74649–60. https://doi.org/10.18632/oncotarget.20301.
Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010;31(2):89–98. https://doi.org/10.1016/j.tips.2009.11.004.
de Groot S, Lugtenberg RT, Cohen D, Welters MJP, Ehsan I, Vreeswijk MPG, et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun. 2020;11(1):3083. https://doi.org/10.1038/s41467-020-16138-3.
Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG, Kofler B. Ketogenic diet in the treatment of cancer - where do we stand? Molecular metabolism. 2020;33:102–21. https://doi.org/10.1016/j.molmet.2019.06.026.
de Gruil N, Pijl H, van der Burg SH, Kroep JR. Short-term fasting synergizes with solid cancer therapy by boosting antitumor immunity. Cancers. 2022;14(6). https://doi.org/10.3390/cancers14061390.
Nussinov R, Tsai CJ, Jang H. Anticancer drug resistance: an update and perspective. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2021;59: 100796. https://doi.org/10.1016/j.drup.2021.100796.
Nurgali K, Jagoe RT, Abalo R. Editorial: Adverse effects of cancer chemotherapy: anything new to improve tolerance and reduce sequelae? Front Pharmacol. 2018;9:245. https://doi.org/10.3389/fphar.2018.00245.
Sahoo AK, Goswami U, Dutta D, Banerjee S, Chattopadhyay A, Ghosh SS. Silver nanocluster embedded composite nanoparticles for targeted prodrug delivery in cancer theranostics. ACS Biomater Sci Eng. 2016;2(8):1395–402. https://doi.org/10.1021/acsbiomaterials.6b00334.
Banerjee S, Sahoo AK, Chattopadhyay A, Ghosh SS. Hydrogel nanocarrier encapsulated recombinant IκBα as a novel anticancer protein therapeutics. RSC Adv. 2013;3(33):14123–31. https://doi.org/10.1039/C3RA23181J.
Banerjee S, Sahoo AK, Chattopadhyay A, Ghosh SS. Recombinant IkappaBalpha-loaded curcumin nanoparticles for improved cancer therapeutics. Nanotechnology. 2014;25(34): 345102. https://doi.org/10.1088/0957-4484/25/34/345102.
Zhang J, Yin Y, Zhang J, Zhang J, Su W, Ma H, et al. Suppression of energy metabolism in cancer cells with nutrient-sensing nanodrugs. Nano Lett. 2022;22(6):2514–20. https://doi.org/10.1021/acs.nanolett.2c00356.
Hafeez U, Gan HK, Scott AM. Monoclonal antibodies as immunomodulatory therapy against cancer and autoimmune diseases. Curr Opin Pharmacol. 2018;41:114–21. https://doi.org/10.1016/j.coph.2018.05.010.
Peng Z, Wangmu T, Li L, Han G, Huang D, Yi P. Combination of berberine and low glucose inhibits gastric cancer through the PP2A/GSK3beta/MCL-1 signaling pathway. Eur J Pharmacol. 2022;922: 174918. https://doi.org/10.1016/j.ejphar.2022.174918.
Vidoni C, Ferraresi A, Esposito A, Maheshwari C, Dhanasekaran DN, Mollace V, et al. Calorie restriction for cancer prevention and therapy: mechanisms, expectations, and efficacy. Journal of cancer prevention. 2021;26(4):224–36. https://doi.org/10.15430/JCP.2021.26.4.224.
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Ishthiaq, I.B., Waseem, M. & Banerjee, S. Understanding the Clinical Link Between Fasting and Response to Cancer Therapy. Curr Pharmacol Rep 8, 290–299 (2022). https://doi.org/10.1007/s40495-022-00293-w
- Cancer therapy
- Gene regulation