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Autophagy and intermittent fasting: the connection for cancer therapy?

Abstract

Cancer is a leading cause of death worldwide, and its incidence is continually increasing. Although anticancer therapy has improved significantly, it still has limited efficacy for tumor eradication and is highly toxic to healthy cells. Thus, novel therapeutic strategies to improve chemotherapy, radiotherapy and targeted therapy are an important goal in cancer research. Macroautophagy (herein referred to as autophagy) is a conserved lysosomal degradation pathway for the intracellular recycling of macromolecules and clearance of damaged organelles and misfolded proteins to ensure cellular homeostasis. Dysfunctional autophagy contributes to many diseases, including cancer. Autophagy can suppress or promote tumors depending on the developmental stage and tumor type, and modulating autophagy for cancer treatment is an interesting therapeutic approach currently under intense investigation. Nutritional restriction is a promising protocol to modulate autophagy and enhance the efficacy of anticancer therapies while protecting normal cells. Here, the description and role of autophagy in tumorigenesis will be summarized. Moreover, the possibility of using fasting as an adjuvant therapy for cancer treatment, as well as the molecular mechanisms underlying this approach, will be presented.

Apoptosis; Autophagy; Fasting; Cancer; Therapy


Autophagy: definition and mechanisms

The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for his initial elucidation of the morphological and molecular mechanisms of autophagy in the 1990s (11. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333(1-2):169-74, http://dx.doi.org/10.1016/0014-5793(93)80398-E.
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). Autophagy is an evolutionarily conserved lysosomal catabolic process by which cells degrade and recycle intracellular endogenous (damaged organelles, misfolded or mutant proteins and macromolecules) and exogenous (viruses and bacteria) components to maintain cellular homeostasis (33. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36(13):1811-36, http://dx.doi.org/10.15252/embj.201796697.
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). The specificity of the cargo and the delivery route to lysosomes distinguishes the three major types of autophagy. Mircroautophagy involves the direct engulfment of cargo in endosomal/lysosomal membrane invaginations (55. Mijaljica D, Prescott M, Devenish RJ. Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy. 2011;7(7):673-82, http://dx.doi.org/10.4161/auto.7.7.14733.
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). Chaperone-mediated autophagy (CMA) recycles soluble proteins with an exposed amino acid motif (KFERQ) that is recognized by the heat shock protein hsc70; these proteins are internalized by binding to lysosomal receptors (LAMP-2A) (66. Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012;22(8):407-17, http://dx.doi.org/10.1016/j.tcb.2012.05.006.
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). Macroautophagy (herein referred to as autophagy) is the best-characterized process; in this process, cytoplasmic constituents are engulfed within double-membrane vesicles called autophagosomes, which subsequently fuse with lysosomes to form autolysosomes, where the cargo are degraded or recycled (33. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36(13):1811-36, http://dx.doi.org/10.15252/embj.201796697.
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Autophagy occurs at basal levels under physiological conditions and can also be upregulated in response to stressful stimuli such as hypoxia, nutritional deprivation, DNA damage, and cytotoxic agents (1111. Kroemer G, Marião G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40(2):280-93, http://dx.doi.org/10.1016/j.molcel.2010.09.023.
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). The molecular machinery that mediates the autophagic process is evolutionarily conserved in higher eukaryotes and regulated by specific genes (ATG genes), which were initially characterized in yeast (1313. Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27:107-32, http://dx.doi.org/10.1146/annurev-cellbio-092910-154005.
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). Each stage is controlled by different protein complexes regulated by the activation or inactivation of several stress-responsive pathways, such as those involving mammalian target of rapamycin (mTOR—nutrient), AMP-activated protein kinase (AMPK—energy) and hypoxia-inducible factors (HIFs—stress) (33. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36(13):1811-36, http://dx.doi.org/10.15252/embj.201796697.
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). Regarding initialization, the activation of the ULK1 complex (ULK1/2, Atg13, FIP200 and Atg101) signals for autophagosome nucleation under the control of the PI3K III complex (PI3KIII, Beclin-1, Atg14/Barkor, Vps15 and Ambra-1), whose activation induces PIP3 (phosphatidyl inositol 3 phosphate) production, which in turn recruits other Atg proteins to form the phagophore (1616. Lin MG, Hurley JH. Structure and function of the ULK1 complex in autophagy. Curr Opin Cell Biol. 2016;39:61-8, http://dx.doi.org/10.1016/j.ceb.2016.02.010.
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). Subsequently, two ubiquitin-like conjugation systems mediate the recruitment of ATG12–ATG5 and microtubule-associated protein light chain 3 (LC3) proteins to the phagophore, allowing its expansion and closure to form the mature autophagosome (1717. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, et al. A protein conjugation system essential for autophagy. Nature. 1998;395(6700):395-8, http://dx.doi.org/10.1038/26506.
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). This process leads to the conversion of the soluble protein LC3-I via conjugation to phosphatidylethanolamine to form an LC3-II membrane-associated form in the cytosol, specifically in the inner and outer membranes of the autophagosome (1818. Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, et al. A ubiquitin-like system mediates protein lipidation. Nature. 2000;408(6811):488-92, http://dx.doi.org/10.1038/35044114.
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). Furthermore, LC3-II can interact with adaptor proteins such as p62 (also known as sequestosome-1/SQSTM1), which directs cargo delivery to autophagosomes for further degradation in lysosomes, the final step of autophagy (2020. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282(33):24131-45, http://dx.doi.org/10.1074/jbc.M702824200.
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Throughout the past decade, autophagy has attracted considerable attention as a potential target of pharmacological agents or dietary interventions that inhibit or activate this process for several human disorders, including infections and inflammatory diseases (2222. Cadwell K. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol. 2016;16(11):661-75, http://dx.doi.org/10.1038/nri.2016.100.
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), neurodegeneration (2323. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al. Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. Neuron. 2017;93(5):1015-34, http://dx.doi.org/10.1016/j.neuron.2017.01.022.
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), metabolic and cardiovascular diseases (2424. Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and Mitophagy in Cardiovascular Disease. Circ Res. 2017;120(11):1812-24, http://dx.doi.org/10.1161/CIRCRESAHA.117.311082.
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), obesity (2525. Lavallard VJ, Meijer AJ, Codogno P, Gual P. Autophagy, signaling and obesity. Pharmacol Res. 2012;66(6):513-25, http://dx.doi.org/10.1016/j.phrs.2012.09.003.
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) and cancer (2626. Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30(17):1913-30, http://dx.doi.org/10.1101/gad.287524.116.
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).

Autophagy and cancer

The role of autophagy in cancer is complex, and its function may vary according to several biological factors, including tumor type, progression stage and genetic landscape, along with oncogene activation and tumor suppressor inactivation (2626. Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30(17):1913-30, http://dx.doi.org/10.1101/gad.287524.116.
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). Thus, autophagy can be related either to the prevention of tumorigenesis or to the enabling of cancer cell adaptation, proliferation, survival and metastasis (2929. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12(6):401-10, http://dx.doi.org/10.1038/nrc3262.
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). The initial indication that autophagy could have an important role in tumor suppression came from several studies exploring the essential autophagy gene BECN1, which encodes the Beclin-1 protein, in different cellular models. Liang et al. (3131. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672-6, http://dx.doi.org/10.1038/45257.
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) demonstrated that BECN1 was frequently monoallelically deleted in ovarian, breast and testicular cancer. Moreover, mice harboring allelic loss of BECN1 had a partial autophagy deficiency and were prone to the development of hepatocarcinoma and lung tumors at an advanced age (3232. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112(12):1809-20, http://dx.doi.org/10.1172/JCI20039.
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,3333. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100(25):15077-82, http://dx.doi.org/10.1073/pnas.2436255100.
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). However, BECN1 is located adjacent to the well-known tumor suppressor gene BRCA1, which is commonly deleted in hereditary breast cancer. These deletions are generally extensive and affect BRCA1 along with several other genes, including BECN1, suggesting that the deletion of BRCA1, not the deletion of BECN1, is the driver mutation in breast cancer (3434. Laddha SV, Ganesan S, Chan CS, White E. Mutational landscape of the essential autophagy gene BECN1 in human cancers. Mol Cancer Res. 2014;12(4):485-90, http://dx.doi.org/10.1158/1541-7786.MCR-13-0614.
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). However, autophagy impairment due to a mosaic deletion of ATG5 induces benign liver tumors, demonstrating that different tissues have different responses to autophagy impairment (3535. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011;25(8):795-800, http://dx.doi.org/10.1101/gad.2016211.
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). Furthermore, the activation of oncogenes (e.g., PI3KCA) and inactivation of tumor suppressors (e.g., PTEN and LKB1) are associated with autophagy inhibition and tumorigenesis (3636. He C, Levine B. The Beclin 1 interactome. Curr Opin Cell Biol. 2010;22(2):140-9, http://dx.doi.org/10.1016/j.ceb.2010.01.001.
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). In general, studies from animal models note that the tumor suppressor function of autophagy is associated with cell protection from oxidative stress, DNA damage, inflammation and the accumulation of dysfunctional organelles. Collectively, these phenomena are important factors that could trigger genomic instabilities leading to tumor development (2929. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12(6):401-10, http://dx.doi.org/10.1038/nrc3262.
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). However, the loss of function of autophagy genes has not yet been identified and demonstrated in humans, raising doubts about the relevance of autophagy to tumor initiation in different types of cancer (2626. Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30(17):1913-30, http://dx.doi.org/10.1101/gad.287524.116.
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). In addition, the autophagic machinery is not a common target of somatic mutations, indicating that autophagy may have a fundamental role in the survival and progression of tumor cells (3939. Lebovitz CB, Robertson AG, Goya R, Jones SJ, Morin RD, Marra MA, et al. Cross-cancer profiling of molecular alterations within the human autophagy interaction network. Autophagy. 2015;11(9):1668-87, http://dx.doi.org/10.1080/15548627.2015.1067362.
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).

Once the tumor is established, the main function of autophagy is to provide a means to cope with cellular stressors, including hypoxia, nutritional and growth factor deprivation and damaging stimuli, thus allowing tumor adaptation, proliferation, survival and dissemination (4040. White E. The role for autophagy in cancer. J Clin Invest. 2015;125(1):42-6, http://dx.doi.org/10.1172/JCI73941.
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). Autophagy, by degrading macromolecules and defective organelles, supplies metabolites and upregulates mitochondrial function, supporting tumor cell viability even in constantly stressful environments (1111. Kroemer G, Marião G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40(2):280-93, http://dx.doi.org/10.1016/j.molcel.2010.09.023.
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,2929. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12(6):401-10, http://dx.doi.org/10.1038/nrc3262.
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). Studies have demonstrated that autophagy increases in hypoxic regions of solid tumors, favoring cell survival. The inhibition of autophagy leads to an intense induction of cell death in these regions (4141. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006;10(1):51-64, http://dx.doi.org/10.1016/j.ccr.2006.06.001.
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,4242. Papandreou I, Lim AL, Laderoute K, Denko NC. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ. 2008;15(10):1572-81, http://dx.doi.org/10.1038/cdd.2008.84.
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). Moreover, tumors frequently have mutations or deletions in the tumor suppressor protein p53, which also favors autophagy induction to recycle intracellular components for tumor growth (4343. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M, et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol. 2008;10(6):676-87, http://dx.doi.org/10.1038/ncb1730.
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). Although the basal autophagy rate is generally low in normal cells under physiological conditions, some tumors show a high level of basal autophagy, reinforcing the prosurvival role of autophagy in cancer (4040. White E. The role for autophagy in cancer. J Clin Invest. 2015;125(1):42-6, http://dx.doi.org/10.1172/JCI73941.
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,4444. Corazzari M, Rapino F, Ciccosanti F, Giglio P, Antonioli M, Conti B, et al. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma. Cell Death Differ. 2015;22(6):946-58, http://dx.doi.org/10.1038/cdd.2014.183.
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). RAS-transformed cancer cells undergo autophagy upregulation to supply metabolic needs and maintain functional mitochondria, which in turn favors tumor establishment (4545. Lock R, Kenific CM, Leidal AM, Salas E, Debnath J. Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion. Cancer Discov. 2014;4(4):466-79, http://dx.doi.org/10.1158/2159-8290.CD-13-0841.
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46. Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell. 2011;22(2):165-78, http://dx.doi.org/10.1091/mbc.e10-06-0500.
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-4747. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 2011;25(5):460-70, http://dx.doi.org/10.1101/gad.2016311.
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). Autophagy also has a supportive role in metastasis by interfering with epithelial-mesenchymal transition constituents to favor tumor cell dissemination (3030. Sharifi MN, Mowers EE, Drake LE, Collier C, Chen H, Zamora M, et al. Autophagy Promotes Focal Adhesion Disassembly and Cell Motility of Metastati Tumor Cells through the Direct Interaction of Paxillin with LC3. Cell Rep. 2016;15(8):1660-72, http://dx.doi.org/10.1016/j.celrep.2016.04.065.
http://dx.doi.org/10.1016/j.celrep.2016....
). Finally, studies have demonstrated that autophagy is commonly induced as a survival mechanism against antitumor treatments, such as chemotherapy, radiotherapy and targeted therapy, contributing to treatment resistance (4848. Chen N, Karantza V. Autophagy as a therapeutic target in cancer. Cancer Biol Ther. 2011;11(2):157-68, http://dx.doi.org/10.4161/cbt.11.2.14622.
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).

Autophagy and cancer therapeutics

Because autophagy can inhibit tumor development or favor tumor growth, progression, invasion and treatment resistance, researchers proposed that autophagy modulation could be a new therapeutic strategy in the treatment of some malignancies (2828. Levy JM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17(9):528-42, http://dx.doi.org/10.1038/nrc.2017.53.
http://dx.doi.org/10.1038/nrc.2017.53...
,4949. Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017;16(7):487-511, http://dx.doi.org/10.1038/nrd.2017.22.
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,5050. Fulda S. Autophagy in Cancer Therapy. Front Oncol. 2017;7:128, http://dx.doi.org/10.3389/fonc.2017.00128.
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).

Recently, we published a review on autophagy and cancer, suggesting that some challenges, such as the incomplete understanding of the relationship between autophagy, tumor resistance, and cell death, as well as the identification of new druggable targets, need to be overcome with the aim of pharmacologically modulating autophagy for cancer treatment (5151. Bincoletto C, Bechara A, Pereira GJ, Santos CP, Antunes F, Peixoto da-Silva J, et al. Interplay between apoptosis and autophagy, a challenging puzzle: new perspectives on antitumor chemotherapies. Chem Biol Interact. 2013;206(2):279-88, http://dx.doi.org/10.1016/j.cbi.2013.09.018.
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). Some of these suggestions are based on the current literature and on previous studies published by our group demonstrating that combining different agents such as selumetinib and cytarabine with autophagy inhibitors (bafilomycin A1, chloroquine or 3-methyladenine) enhanced the activity of selumetinib and cytarabine against colorectal cancer cells (5252. Grasso S, Pereira GJ, Palmeira-Dos-Santos C, Calgarotto AK, Martínez-Lacaci I, Ferragut JA, et al. Autophagy regulates Selumetinib (AZD6244) induced-apoptosis in colorectal cancer cells. Eur J Med Chem. 2016;122:611-8, http://dx.doi.org/10.1016/j.ejmech.2016.06.043.
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) and leukemia cells (5353. Palmeira dos Santos C, Pereira GJ, Barbosa CM, Jurkiewicz A, Smaili SS, Bincoletto C. Comparative study of autophagy inhibition by 3MA and CQ on Cytarabine-induced death of leukaemia cells. J Cancer Res Clin Oncol. 2014;140(6):909-20, http://dx.doi.org/10.1007/s00432-014-1640-4.
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), respectively. Autophagy was also observed in melanoma cells under treatment with palladium complex drugs (5454. Gigli R, Pereira GJ, Antunes F, Bechara A, Garcia DM, Spindola DG, et al. The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy. Eur J Med Chem. 2016;107:245-54, http://dx.doi.org/10.1016/j.ejmech.2015.11.008.
http://dx.doi.org/10.1016/j.ejmech.2015....
), indicating the importance of investigating the relationship between autophagy and apoptosis during new drug development. Additionally, other studies demonstrated that inhibiting autophagy by chloroquine in combination with sorafenib in an in vitro model of glioblastoma (5555. Liu X, Sun K, Wang H, Dai Y. Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma. Cell Mol Neurobiol. 2016;36(7):1197-208, http://dx.doi.org/10.1007/s10571-015-0318-z.
http://dx.doi.org/10.1007/s10571-015-031...
) and in combination with temozolomide in melanoma patients augmented antitumor treatment efficacy (5656. Rangwala R, Leone R, Chang YC, Fecher LA, Schuchter LM, Kramer A, et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy. 2014;10(8):1369-79, http://dx.doi.org/10.4161/auto.29118.
http://dx.doi.org/10.4161/auto.29118...
). The inhibition of autophagy was also demonstrated to potentiate the response to radiotherapy in ovarian (5757. Liang B, Kong D, Liu Y, Liang N, He M, Ma S, et al. Autophagy inhibition plays the synergetic killing roles with radiation in the multi-drug resistant SKVCR ovarian cancer cells. Radiat Oncol. 2012;7:213, http://dx.doi.org/10.1186/1748-717X-7-213.
http://dx.doi.org/10.1186/1748-717X-7-21...
) and esophageal cancer (5858. Chen Y, Li X, Guo L, Wu X, He C, Zhang S, et al. Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer. Mol Med Rep. 2015;12(2):1645-52, http://dx.doi.org/10.3892/mmr.2015.3623.
http://dx.doi.org/10.3892/mmr.2015.3623...
). The efficacy of autophagy in favoring cell death has been demonstrated in many other cancer models, such as breast cancer, leukemia, prostate cancer, and myeloma (4848. Chen N, Karantza V. Autophagy as a therapeutic target in cancer. Cancer Biol Ther. 2011;11(2):157-68, http://dx.doi.org/10.4161/cbt.11.2.14622.
http://dx.doi.org/10.4161/cbt.11.2.14622...
,4949. Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017;16(7):487-511, http://dx.doi.org/10.1038/nrd.2017.22.
http://dx.doi.org/10.1038/nrd.2017.22...
). However, to date, clinical trials have not demonstrated that autophagy inhibition associated with anticancer therapy provided reliable therapeutic benefits to patients (5959. Gewirtz DA. The Challenge of Developing Autophagy Inhibition as a Therapeutic Strategy. Cancer Res. 2016;76(19):5610-4, http://dx.doi.org/10.1158/0008-5472.CAN-16-0722.
http://dx.doi.org/10.1158/0008-5472.CAN-...
). Currently, protocols targeting autophagy induction instead of autophagy blockade are under intense investigation in oncology (2828. Levy JM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17(9):528-42, http://dx.doi.org/10.1038/nrc.2017.53.
http://dx.doi.org/10.1038/nrc.2017.53...
,5050. Fulda S. Autophagy in Cancer Therapy. Front Oncol. 2017;7:128, http://dx.doi.org/10.3389/fonc.2017.00128.
http://dx.doi.org/10.3389/fonc.2017.0012...
,6060. Galluzzi L, Bravo-San Pedro JM, Demaria S, Formenti SC, Kroemer G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol. 2017;14(4):247-58, http://dx.doi.org/10.1038/nrclinonc.2016.183.
http://dx.doi.org/10.1038/nrclinonc.2016...
). Nevertheless, no drug currently licensed by any regulatory agency was developed for autophagy modulation, although several approved agents indeed modulate autophagy to some extent (6161. Vakifahmetoglu-Norberg H, Xia HG, Yuan J. Pharmacologic agents targeting autophagy. J Clin Invest. 2015;125(1):5-13, http://dx.doi.org/10.1172/JCI73937.
http://dx.doi.org/10.1172/JCI73937...
,6262. Ha J, Kim J. Novel pharmacological modulators of autophagy: an updated patent review (2012-2015). Expert Opin Ther Pat. 2016;26(11):1273-89, http://dx.doi.org/10.1080/13543776.2016.1217996.
http://dx.doi.org/10.1080/13543776.2016....
).

How does dietary restriction modulate autophagy and cancer therapy?

In preclinical studies, dietary restriction (DR) has been shown to extend the lifespan and reduce the development of age-related diseases such as diabetes, cancer, and neurodegenerative and cardiovascular diseases (6363. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 2017;15(1):106, http://dx.doi.org/10.1186/s12916-017-0873-x.
http://dx.doi.org/10.1186/s12916-017-087...
). DR promotes metabolic and cellular changes in organisms from prokaryotes to humans that allow adaptation to periods of limited nutrient availability (6464. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181-92, http://dx.doi.org/10.1016/j.cmet.2013.12.008.
http://dx.doi.org/10.1016/j.cmet.2013.12...
). The main changes include decreased blood glucose levels and growth factor signaling and the activation of stress resistance pathways affecting cell growth, energy metabolism, and protection against oxidative stress, inflammation and cell death (6464. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181-92, http://dx.doi.org/10.1016/j.cmet.2013.12.008.
http://dx.doi.org/10.1016/j.cmet.2013.12...
,6565. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58, http://dx.doi.org/10.1016/j.arr.2016.10.005.
http://dx.doi.org/10.1016/j.arr.2016.10....
). Nutrient starvation also activates autophagy in most cultured cells and organs, such as the liver and muscle, as an adaptive mechanism to stressful conditions (1111. Kroemer G, Marião G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40(2):280-93, http://dx.doi.org/10.1016/j.molcel.2010.09.023.
http://dx.doi.org/10.1016/j.molcel.2010....
,6666. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004;15(3):1101-11, http://dx.doi.org/10.1091/mbc.e03-09-0704.
http://dx.doi.org/10.1091/mbc.e03-09-070...
).

Studies demonstrate that dietary interventions can reduce tumor incidence and potentiate the effectiveness of chemo- and radiotherapy in different tumor models, highlighting dietary manipulation as a possible adjunct to standard cancer therapies (6363. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 2017;15(1):106, http://dx.doi.org/10.1186/s12916-017-0873-x.
http://dx.doi.org/10.1186/s12916-017-087...
,6565. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58, http://dx.doi.org/10.1016/j.arr.2016.10.005.
http://dx.doi.org/10.1016/j.arr.2016.10....
). Among the many diet regimens that have been assessed, caloric restriction (CR) and fasting are the methods under intense investigation in oncology (6363. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 2017;15(1):106, http://dx.doi.org/10.1186/s12916-017-0873-x.
http://dx.doi.org/10.1186/s12916-017-087...
,6565. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58, http://dx.doi.org/10.1016/j.arr.2016.10.005.
http://dx.doi.org/10.1016/j.arr.2016.10....
,6767. Simone BA, Champ CE, Rosenberg AL, Berger AC, Monti DA, Dicker AP, et al. Selectively starving cancer cells through dietary manipulation: methods and clinical implications. Future Oncol. 2013;9(7):959-76, http://dx.doi.org/10.2217/fon.13.31.
http://dx.doi.org/10.2217/fon.13.31...
). CR is defined as a chronic reduction in the daily caloric intake by 20-40% without the incurrence of malnutrition and with the maintenance of meal frequency (6868. Speakman JR, Mitchell SE. Caloric restriction. Mol Aspects Med. 2011;32(3):159-221, http://dx.doi.org/10.1016/j.mam.2011.07.001.
http://dx.doi.org/10.1016/j.mam.2011.07....
). In contrast, fasting is characterized by the complete deprivation of food but not water, with intervening periods of normal food intake. Based on the duration, fasting can be classified as (i) intermittent fasting (IF—e.g., alternate day fasting (≥16 hours) or 48 hours of fasting/week) or (ii) periodic fasting (PF—e.g., a minimum of 3 days of fasting every 2 or more weeks) (6565. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58, http://dx.doi.org/10.1016/j.arr.2016.10.005.
http://dx.doi.org/10.1016/j.arr.2016.10....
). In this article, we do not review CR studies that have been reviewed elsewhere (6363. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 2017;15(1):106, http://dx.doi.org/10.1186/s12916-017-0873-x.
http://dx.doi.org/10.1186/s12916-017-087...
,6868. Speakman JR, Mitchell SE. Caloric restriction. Mol Aspects Med. 2011;32(3):159-221, http://dx.doi.org/10.1016/j.mam.2011.07.001.
http://dx.doi.org/10.1016/j.mam.2011.07....
,6969. Kopeina GS, Senichkin VV, Zhivotovsky B. Caloric restriction - A promising anti-cancer approach: From molecular mechanisms to clinical trials. Biochim Biophys Acta Rev Cancer. 2017;1867(1):29-41, http://dx.doi.org/10.1016/j.bbcan.2016.11.002.
http://dx.doi.org/10.1016/j.bbcan.2016.1...
); instead, we focus on studies using IF protocols as an adjuvant to cancer treatment in animals and humans.

Recently, studies in in vitro and in vivo models have shown that intermittent fasting improved the chemotherapeutic response to cisplatin, doxorubicin, cyclophosphamide (7070. 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):124ra27, http://dx.doi.org/10.1126/scitranslmed.3003293.
http://dx.doi.org/10.1126/scitranslmed.3...
), oxaliplatin (7171. Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, et al. Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget. 2015;6(14):11806-19, http://dx.doi.org/10.18632/oncotarget.3688.
http://dx.doi.org/10.18632/oncotarget.36...
), sorafenib (7272. Lo Re O, Panebianco C, Porto S, Cervi C, Rappa F, Di Biase S, et al. Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells. J Cell Physiol. 2018;233(2):1202-12, http://dx.doi.org/10.1002/jcp.25987.
http://dx.doi.org/10.1002/jcp.25987...
), mitoxantrone (7373. 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, http://dx.doi.org/10.1016/j.ccell.2016.05.016.
http://dx.doi.org/10.1016/j.ccell.2016.0...
), gemcitabine (7474. D’Aronzo M, Vinciguerra M, Mazza T, Panebianco C, Saracino C, Pereira SP, et al. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. Oncotarget. 2015;6(21):18545-57, http://dx.doi.org/10.18632/oncotarget.4186.
http://dx.doi.org/10.18632/oncotarget.41...
), etoposide (7575. 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, http://dx.doi.org/10.1073/pnas.0708100105.
http://dx.doi.org/10.1073/pnas.070810010...
), temozolomide (7676. 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, http://dx.doi.org/10.1371/journal.pone.0044603.
http://dx.doi.org/10.1371/journal.pone.0...
) and tyrosine kinase inhibitors (7777. Caffa I, D’Agostino V, Damonte P, Soncini D, Cea M, Monacelli F, et al. Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget. 2015;6(14):11820-32, http://dx.doi.org/10.18632/oncotarget.3689.
http://dx.doi.org/10.18632/oncotarget.36...
) in models of glioma, neuroblastoma, melanoma, fibrosarcoma and breast cancer, colon cancer, pancreatic cancer, hepatocellular cancer and lung cancer. IF has also been shown to improve the radiosensitivity of glioma (7676. 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, http://dx.doi.org/10.1371/journal.pone.0044603.
http://dx.doi.org/10.1371/journal.pone.0...
) and breast cancer (7878. 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, http://dx.doi.org/10.4161/cc.25016.
http://dx.doi.org/10.4161/cc.25016...
) in mice. Interestingly, fasting in combination with cytotoxic agents elicited differential responses in normal and cancer cells, a phenomenon known as differential stress resistance (DSR). For DSR, normal cells prioritize maintenance pathways and inactivate growth factor signaling when nutrients are absent. In contrast, cancer cells, due to oncogene activation, do not inhibit stress resistance pathways, thus becoming vulnerable to cytotoxic treatment (7070. 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):124ra27, http://dx.doi.org/10.1126/scitranslmed.3003293.
http://dx.doi.org/10.1126/scitranslmed.3...
,7575. 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, http://dx.doi.org/10.1073/pnas.0708100105.
http://dx.doi.org/10.1073/pnas.070810010...
). IF, by reducing the circulating glucose levels, protected mice from doxorubicin toxicity and particularly promoted cardioprotection mediated in part by EGFR1-dependent transcriptional regulation of atrial natriuretic peptide and B-type natriuretic peptide in heart tissue (7979. 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, http://dx.doi.org/10.1371/journal.pbio.2001951.
http://dx.doi.org/10.1371/journal.pbio.2...
). As demonstrated by Tinkum et al. (8080. Tinkum KL, Stemler KM, White LS, Loza AJ, Jeter-Jones S, Michalski BM, et al. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival. Proc Natl Acad Sci U S A. 2015;112(51):E7148-54, http://dx.doi.org/10.1073/pnas.1509249112.
http://dx.doi.org/10.1073/pnas.150924911...
), IF also facilitated DNA repair activation mechanisms and preserved small intestinal (SI) stem cell viability as well SI architecture and barrier function after exposure to high-dose etoposide, suggesting that fasting can be applied to reduce side effects and toxicity in patients undergoing chemotherapy.

Although the results of combining IF with anticancer drugs are encouraging, the molecular mechanisms are not completely clear. Lee et al. (8181. 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. Cancer Res. 2010;70(4):1564-72, http://dx.doi.org/10.1158/0008-5472.CAN-09-3228.
http://dx.doi.org/10.1158/0008-5472.CAN-...
) demonstrated that IF (48-hour fasting) reduced the glucose and IGF-1 levels by 60% and 70%, respectively, in a breast cancer animal model. In a colon cancer model, IF inhibited tumor growth without causing permanent weight loss and decreased M2 polarization of tumor-associated macrophages in mice. In vitro data showed autophagy induction and CD73 downregulation, followed by a decrease in extracellular adenosine and the inhibition of M2 polarization due to the inactivation of JAK1/STAT3 (8282. 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, http://dx.doi.org/10.18632/oncotarget.20301.
http://dx.doi.org/10.18632/oncotarget.20...
).

When IF cycles were combined with chemotherapy, tumor growth was slowed and overall survival was prolonged in breast cancer, melanoma and neuroblastoma animal models (7070. 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):124ra27, http://dx.doi.org/10.1126/scitranslmed.3003293.
http://dx.doi.org/10.1126/scitranslmed.3...
). The in vitro data showed that this therapeutic combination resulted in increased Akt and S6 kinase phosphorylation, caspase-3 cleavage and apoptosis induction in cancer cells but not in normal cells (7070. 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):124ra27, http://dx.doi.org/10.1126/scitranslmed.3003293.
http://dx.doi.org/10.1126/scitranslmed.3...
). Other studies demonstrated that the combination of IF and oxaliplatin also reduced tumor growth and glucose uptake in vivo and resulted in downregulated aerobic glycolysis followed by augmented oxidative phosphorylation, leading to increased oxidative stress, decreased ATP synthesis and cell death in colon cancer cell models (7171. Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, et al. Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget. 2015;6(14):11806-19, http://dx.doi.org/10.18632/oncotarget.3688.
http://dx.doi.org/10.18632/oncotarget.36...
). Furthermore, Our group also demonstrated that nutritional deprivation enhanced the sensitivity of both wild type and BRAFV600E human melanoma cells to cisplatin treatment followed by ROS production and mitochondrial perturbation leading to apoptosis without autophagy involvement in the cell death process (8383. Antunes F, Corazzari M, Pereira G, Fimia GM, Piacentini M, Smaili S. Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death. Biochem Biophys Res Commun. 2017;485(1):16-22, http://dx.doi.org/10.1016/j.bbrc.2016.09.149.
http://dx.doi.org/10.1016/j.bbrc.2016.09...
). Pietrocola et al. (7373. 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, http://dx.doi.org/10.1016/j.ccell.2016.05.016.
http://dx.doi.org/10.1016/j.ccell.2016.0...
) showed that IF improved the chemotherapeutic response to mitoxantrone and oxaliplatin in murine fibrosarcoma, reducing tumor growth in immunocompetent mice. This group also showed that the impairment of tumor growth was dependent on the cellular immune system as well as on autophagy; IF + chemotherapy could not impair tumor growth in either athymic nu/nu mice or tumor cells after autophagy deficiency was induced by Atg5 knockdown.

The combination of IF and tyrosine kinase inhibitors such as erlotinib, gefitinib, lapatinib, crizotinib and regorafenib promoted the sustained inhibition of the MAPK pathway, leading to antiproliferative effects in breast, colorectal and lung cancer cell models, as well as to the inhibition of tumor growth in an in vivo model of lung cancer (7777. Caffa I, D’Agostino V, Damonte P, Soncini D, Cea M, Monacelli F, et al. Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget. 2015;6(14):11820-32, http://dx.doi.org/10.18632/oncotarget.3689.
http://dx.doi.org/10.18632/oncotarget.36...
). The combination of IF and the multi-tyrosine kinase inhibitor sorafenib exhibited an additive effect in inhibiting hepatocarcinoma cell proliferation and glucose uptake as well as downregulating the MAPK pathway and the gene expression of BIRC5, DKK1, TRIB3 and VEGF, which are commonly altered in hepatocarcinoma cells (7272. Lo Re O, Panebianco C, Porto S, Cervi C, Rappa F, Di Biase S, et al. Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells. J Cell Physiol. 2018;233(2):1202-12, http://dx.doi.org/10.1002/jcp.25987.
http://dx.doi.org/10.1002/jcp.25987...
). In pancreatic cancer, fasting increased the uptake of gemcitabine due to enhanced levels of its transporter (hENT1), thus potentiating cell death. In a xenograft pancreatic cancer model, fasting cycles and gemcitabine treatment induced a reduction in tumor growth of more than 40% (7474. D’Aronzo M, Vinciguerra M, Mazza T, Panebianco C, Saracino C, Pereira SP, et al. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. Oncotarget. 2015;6(21):18545-57, http://dx.doi.org/10.18632/oncotarget.4186.
http://dx.doi.org/10.18632/oncotarget.41...
).

A small pilot study comprising 10 patients diagnosed with breast, prostate, esophageal or lung cancer in advanced stages suggested that periods of intermittent fasting before and after chemotherapy reduces the self-reported side effects of therapy, especially those associated with the gastrointestinal system, as well as weakness and fatigue. Additionally, no negative effect on the chemotherapy response or persistent weight loss was observed (8484. 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, http://dx.doi.org/10.18632/aging.100114.
http://dx.doi.org/10.18632/aging.100114...
,8585. Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD. Fasting and differential chemotherapy protection in patients. Cell Cycle. 2010;9(22):4474-6, http://dx.doi.org/10.4161/cc.9.22.13954.
http://dx.doi.org/10.4161/cc.9.22.13954...
). In another clinical trial, the combination of IF and platinum-based chemotherapy promoted pathologic complete or partial radiographic responses in the majority of patients affected by different stages and types of tumors, such as ovarian, uterine, breast and urothelial cancer. A reduction in leukocyte DNA damage, in addition to decreased levels of circulating IGF-1, has also been reported (8686. Dorff TB, Groshen S, Garcia A, Shah M, Tsao-Wei D, Pham H, et al. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 2016;16:360, http://dx.doi.org/10.1186/s12885-016-2370-6.
http://dx.doi.org/10.1186/s12885-016-237...
). Both studies established the feasibility of IF in humans and suggested that combining IF with cytotoxic agents in the clinical context is safe and may be well-tolerated by patients, although this regimen may be psychologically uncomfortable for some individuals (8484. 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, http://dx.doi.org/10.18632/aging.100114.
http://dx.doi.org/10.18632/aging.100114...
85. Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD. Fasting and differential chemotherapy protection in patients. Cell Cycle. 2010;9(22):4474-6, http://dx.doi.org/10.4161/cc.9.22.13954.
http://dx.doi.org/10.4161/cc.9.22.13954...
86. Dorff TB, Groshen S, Garcia A, Shah M, Tsao-Wei D, Pham H, et al. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 2016;16:360, http://dx.doi.org/10.1186/s12885-016-2370-6.
http://dx.doi.org/10.1186/s12885-016-237...
-8787. Michalsen A, Hoffmann B, Moebus S, Bäcker M, Langhorst J, Dobos GJ. Incorporation of fasting therapy in an integrative medicine ward: evaluation of outcome, safety, and effects on lifestyle adherence in a large prospective cohort study. J Altern Complement Med. 2005;11(4):601-7, http://dx.doi.org/10.1089/acm.2005.11.601.
http://dx.doi.org/10.1089/acm.2005.11.60...
). Currently, other clinical trials involving IF combined with chemotherapy in cancer patients are underway; these trials are summarized in Table 1. The results of these trials will be essential for a better evaluation of the clinical potential and application of this new therapeutic strategy.

Table 1
Completed and current clinical trials investigating the effects of fasting as adjunct therapy to anti-cancer treatment.

Another novel pharmacological therapeutic strategy currently being investigated to treat cancer is the combination of caloric restriction mimetics (CRMs) with cytotoxic agents. CRMs are compounds that have different chemical structures and mimic the biochemical and functional effects of CR, such as the activation of AMPK and inhibition of mTOR leading to autophagy induction, the depletion of acetyl-CoA and ATP, and the reduced utilization of glucose, without eliciting the discomfort of CR (8888. Madeo F, Pietrocola F, Eisenberg T, Kroemer G. Caloric restriction mimetics: towards a molecular definition. Nat Rev Drug Discov. 2014;13(10):727-40, http://dx.doi.org/10.1038/nrd4391.
http://dx.doi.org/10.1038/nrd4391...
). Several studies demonstrated the tumor-suppressive effects of CRM agents, for example, 2-deoxy-glucose (8989. Dwarakanath B, Jain V. Targeting glucose metabolism with 2-deoxy-D-glucose for improving cancer therapy. Future Oncol. 2009;5(5):581-5, http://dx.doi.org/10.2217/fon.09.44.
http://dx.doi.org/10.2217/fon.09.44...
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http://dx.doi.org/10.3892/ol.2017.6739...
), in combination with antitumor treatments in different cancer models. The possible connections between fasting and anticancer therapy potentiation in tumor cells are summarized in Figure 1.

Figure 1
Presumable molecular mechanisms induced by fasting and anticancer treatment to promote intracellular changes and autophagy induction in tumor cells. I) Fasting may oppose the Warburg effect (glucose breakdown by glycolysis even in the presence of oxygen), favoring oxidative phosphorylation in tumor cells and resulting in increased ROS production and reduced levels of lactate and possibly ATP. The increase in the ADP/ATP ratio can activate the AMPK pathway, leading to autophagy induction. Moreover, the sustained stressful environment can result in cell death induction. II) Several tumors harbor mutations that favor MAPK pathway hyperactivation, which enables tumor cell growth, survival and proliferation. Therapies targeting this pathway, as well as fasting, may result in the downregulation of this pathway alongside a reduction in AKT and mTOR activation, resulting in autophagy induction and cell death. III) Furthermore, fasting potentiates the detrimental effects of chemotherapy, such as DNA damage, thus activating the cell death machinery, deregulating pro- and antiapoptotic proteins, and inducing mitochondrial alterations and caspase activation, which in turn culminates in apoptosis.

In this review, we highlighted the concepts of autophagy, especially in relation to tumorigenesis, as well as the potential of autophagy as a therapeutic target in the treatment of different malignancies. We also pointed out the possibility of using dietary manipulation as an autophagy modulator as well as a cost-effective intervention to increase therapeutic response in the challenging oncologic arena. Furthermore, fasting may protect normal cells from the toxicity of anticancer agents, reducing side effects in patients and increasing the detrimental effects of chemotherapy, radiotherapy and targeted therapy on tumor cells. However, additional studies are required to better understand the molecular mechanisms evoked by fasting, aiming to identify the context in which fasting may be beneficial as an adjunct to cancer treatment. Moreover, further knowledge may also lead to the development of novel pharmacological protocols that replicate effects similar to those of fasting and are more suitable for different oncologic patients.

ACKNOWLEDGMENTS

The authors are grateful for the financial support given by the Fundação de Amparo è Pesquisa do Estado de São Paulo (FAPESP) (08/11515-3 and 13/20073-2 by Smaili SS), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES).

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Publication Dates

  • Publication in this collection
    2018

History

  • Received
    30 May 2018
  • Accepted
    25 Sept 2018
Creative Common - by 4.0
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