Caloric restriction - A promising anti-cancer approach: From molecular mechanisms to clinical trials

Biochimica et Biophysica Acta - Reviews on Cancer

Volumn 1867, Issue 1, 2017, Pages 29-41

  Kopeina, Gelina S ^a   Senichkin, Vyacheslav V ^a   Zhivotovsky, Boris ^a,b  

^a MOSCOW STATE UNIVERSITY   (Russian Federation)

^b KAROLINSKA INSTITUTE   (Sweden)

Author keywords

Caloric restriction; Cancer; Chemotherapy; Programmed cell death

Indexed keywords

ANTINEOPLASTIC AGENT; CURCUMIN; EVEROLIMUS; METFORMIN; QUERCETIN; RESVERATROL; RIDAFOROLIMUS; TEMSIROLIMUS;

ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AUTOPHAGY; BREAST CANCER; CALORIC RESTRICTION; CANCER CELL; CANCER INHIBITION; CANCER STAGING; CANCER SURVIVAL; CARCINOGENESIS; CASTRATION RESISTANT PROSTATE CANCER; CELL DEATH; CELL METABOLISM; CELL STRESS; CELL SURVIVAL; CLINICAL TRIAL (TOPIC); COLORECTAL ADENOMA; COLORECTAL CANCER; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; ENDOMETRIUM CANCER; FATTY ACID OXIDATION; FOLLICULAR LYMPHOMA; GASTROENTEROPANCREATIC NEUROENDOCRINE TUMOR; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; IN VITRO STUDY; IN VIVO STUDY; KETOGENIC DIET; KIDNEY CARCINOMA; LIFESTYLE MODIFICATION; MALIGNANT NEOPLASTIC DISEASE; MANTLE CELL LYMPHOMA; MENINGIOMA; METASTATIC COLORECTAL CANCER; MOLECULARLY TARGETED THERAPY; NON SMALL CELL LUNG CANCER; NONHODGKIN LYMPHOMA; OBESITY; OUTCOME ASSESSMENT; PANCREAS CANCER; PANCREATIC NEUROENDOCRINE TUMOR; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SOFT TISSUE SARCOMA; SOLID TUMOR; SUBEPENDYMAL GIANT CELL ASTROCYTOMA; THERAPY EFFECT; TREATMENT RESPONSE; ANIMAL; CELL PROLIFERATION; DIET THERAPY; DRUG EFFECTS; NEOPLASMS; PROCEDURES;

ANIMALS; ANTINEOPLASTIC AGENTS; CALORIC RESTRICTION; CELL DEATH; CELL PROLIFERATION; HUMANS; NEOPLASMS;

EID: 85002769483     PISSN: 0304419X     EISSN: 18792561     Source Type: Journal    
DOI: 10.1016/j.bbcan.2016.11.002     Document Type: Review

References (166)

1. [1] Obesity and overweight, fact sheets. http://www.who.int/mediacentre/factsheets/fs311/en/, 2015.
2. [2] Fontana, L., Partridge, L., Longo, V.D., Extending healthy life span-from yeast to humans. Science 328 (2010), 321–326.
3. [3] Colman, R.J., Beasley, T.M., Kemnitz, J.W., Johnson, S.C., Weindruch, R., Anderson, R.M., Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 5 (2014), 355–357.
4. [4] Mattison, J.A., Roth, G.S., Beasley, T.M., Tilmont, E.M., Handy, A.M., Herbert, R.L., Longo, D.L., Allison, D.B., Young, J.E., Bryant, M., Barnard, D., Ward, W.F., Qi, W., Ingram, D.K., de Cabo, R., Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489 (2012), 318–321.
5. [5] Bodkin, N.L., Alexander, T.M., Ortmeyer, H.K., Johnson, E., Hansen, B.C., Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. J. Gerontol. A Biol. Sci. Med. Sci. 58 (2003), 212–219.
6. [6] Willcox, D.C., Willcox, B.J., Todoriki, H., Curb, J.D., Suzuki, M., Caloric restriction and human longevity: what can we learn from the Okinawans?. Biogerontology 7 (2006), 173–177.
7. [7] Phelan, J.P., Rose, M.R., Why dietary restriction substantially increases longevity in animal models but won't in humans. Ageing Res. Rev. 4 (2005), 339–350.
8. [8] Anderson, R.M., Shanmuganayagam, D., Weindruch, R., Caloric restriction and aging: studies in mice and monkeys. Toxicol. Pathol. 37 (2009), 47–51.
9. [9] Colman, R.J., Anderson, R.M., Johnson, S.C., Kastman, E.K., Kosmatka, K.J., Beasley, T.M., Allison, D.B., Cruzen, C., Simmons, H.A., Kemnitz, J.W., Weindruch, R., Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325 (2009), 201–204.
10. [10] Lozano, R., Naghavi, M., Foreman, K., Lim, S., Shibuya, K., Aboyans, V., Abraham, J., Murray, C.J., et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380 (2012), 2095–2128.
11. [11] Berger, N.A., Obesity and cancer pathogenesis. Ann. N. Y. Acad. Sci. 1311 (2014), 57–76.
12. [12] Eheman, C., Henley, S.J., Ballard-Barbash, R., Jacobs, E.J., Schymura, M.J., Noone, A.-M., Pan, L., Anderson, R.N., Fulton, J.E., Kohler, B.A., Jemal, A., Ward, E., Plescia, M., Ries, L.A.G., Edwards, B.K., Annual Report to the Nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer 118 (2012), 2338–2366.
13. [13] De Lorenzo, M.S., Baljinnyam, E., Vatner, D.E., Abarzúa, P., Vatner, S.F., Rabson, A.B., Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 32 (2011), 1381–1387.
14. [14] 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 9 (2014), 115–147.
15. [15] Michels, K.B., Ekbom, A., Caloric restriction and incidence of breast cancer. JAMA 291 (2004), 1226–1230.
16. [16] Fontana, L., Villareal, D.T., Das, S.K., Smith, S.R., Meydani, S.N., Pittas, A.G., Klein, S., Bhapkar, M., Rochon, J., Ravussin, E., Holloszy, J.O., CALERIE Study Group, Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: a randomized clinical trial. Aging Cell 15 (2016), 22–27.
17. [17] Lee, C., Raffaghello, L., Brandhorst, S., Safdie, F.M., Bianchi, G., Martin-Montalvo, A., Pistoia, V., Wei, M., Hwang, S., Merlino, A., Emionite, L., de Cabo, R., Longo, V.D., Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med., 4, 2012, 124ra27.
18. [18] Raffaghello, L., Lee, C., Safdie, F.M., Wei, M., Madia, F., Bianchi, G., Longo, V.D., Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 8215–8220.
19. [19] Yang, L., Licastro, D., Cava, E., Veronese, N., Spelta, F., Rizza, W., Bertozzi, B., Villareal, D.T., Hotamisligil, G.S., Holloszy, J.O., Fontana, L., Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 14 (2016), 422–428.
20. [20] Hanahan, D., Weinberg, R.A., The hallmarks of cancer. Cell 100 (2000), 57–70.
21. [21] Pollak, M.N., Schernhammer, E.S., Hankinson, S.E., Insulin-like growth factors and neoplasia. Nat. Rev. Cancer 4 (2004), 505–518.
22. [22] S. Yakar, D. Leroith, P. Brodt, The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: lessons from animal models., Cytokine Growth Factor Rev. 16 (n.d.) 407–20.
23. [23] Green, D.R., Galluzzi, L., Kroemer, G., Cell biology. Metabolic control of cell death. Science, 345, 2014, 1250256.
24. [24] Malley, C.O., Pidgeon, G.P., The mTOR pathway in obesity driven gastrointestinal cancers: potential targets and clinical trials. BBA Clin. 5 (2016), 29–40.
25. [25] Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation. Cell 144 (2011), 646–674.
26. [26] Curry, N.L., Mino-Kenudson, M., Oliver, T.G., Yilmaz, O.H., Yilmaz, V.O., Moon, J.Y., Jacks, T., Sabatini, D.M., Kalaany, N.Y., Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction. Cancer Discov. 3 (2013), 908–921.
27. [27] Johnson, S.C., Rabinovitch, P.S., Kaeberlein, M., mTOR is a key modulator of ageing and age-related disease. Nature 493 (2013), 338–345.
28. [28] Yuan, T.L., Cantley, L.C., PI3K pathway alterations in cancer: variations on a theme. Oncogene 27 (2008), 5497–5510.
29. [29] Jiang, B.-H., Liu, L.-Z., PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim. Biophys. Acta 1784 (2008), 150–158.
30. [30] Cullingford, T.E., The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders. Prostaglandins Leukot. Essent. Fat. Acids 70 (2004), 253–264.
31. [31] Warburg, O., On the origin of cancer cells. Science 123 (1956), 309–314.
32. [32] Vamecq, J., Colet, J.-M., Vanden Eynde, J.J., Briand, G., Porchet, N., Rocchi, S., PPARs: interference with Warburg' effect and clinical anticancer trials. PPAR Res. 2012 (2012), 1–23.
33. [33] D'Angelo, L., Piazzi, G., Pacilli, A., Prossomariti, A., Fazio, C., Montanaro, L., Graziani, G., Fogliano, V., Munarini, A., Bianchi, F., Belluzzi, A., Bazzoli, F., Ricciardiello, L., A combination of eicosapentaenoic acid-free fatty acid, epigallocatechin-3-gallate and proanthocyanidins has a strong effect on mTOR signaling in colorectal cancer cells. Carcinogenesis 35 (2014), 2314–2320.
34. [34] Abu Aboud, O., Donohoe, D., Bultman, S., Fitch, M., Riiff, T., Hellerstein, M., Weiss, R.H., PPARα inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth. Am. J. Phys. Cell Physiol. 308 (2015), C890–C898.
35. [35] Panigrahy, D., Kaipainen, A., Huang, S., Butterfield, C.E., Barnés, C.M., Fannon, M., Laforme, A.M., Chaponis, D.M., Folkman, J., Kieran, M.W., PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 985–990.
36. [36] Shackelford, D.B., Shaw, R.J., The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9 (2009), 563–575.
37. [37] Faubert, B., Boily, G., Izreig, S., Griss, T., Samborska, B., Dong, Z., Dupuy, F., Chambers, C., Fujii, N., et al. AMPK is a negative regulator of the warburg effect and suppresses tumor growth in vivo. Cell Metab. 17 (2013), 113–124.
38. [38] Leprivier, G., Remke, M., Rotblat, B., Dubuc, A., Mateo, A.-R.F., Kool, M., Agnihotri, S., Stiernagle, T., et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153 (2013), 1064–1079.
39. [39] Shaw, R.J., LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxford) 196 (2009), 65–80.
40. [40] Vassilopoulos, A., Fritz, K.S., Petersen, D.R., Gius, D., The human sirtuin family: evolutionary divergences and functions. Hum. Genomics 5 (2011), 485–496.
41. [41] Fujitsuka, N., Asakawa, A., Morinaga, A., Amitani, M.S., Amitani, H., Katsuura, G., Sawada, Y., Sudo, Y., Uezono, Y., Mochiki, E., Sakata, I., Sakai, T., Hanazaki, K., Yada, T., Yakabi, K., Sakuma, E., Ueki, T., Niijima, A., Nakagawa, K., Okubo, N., Takeda, H., Asaka, M., Inui, A., Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol. Psychiatry 21 (2016), 1613–1623.
42. [42] Cohen, H.Y., Miller, C., Bitterman, K.J., Wall, N.R., Hekking, B., Kessler, B., Howitz, K.T., Gorospe, M., de Cabo, R., Sinclair, D.A., Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305 (2004), 390–392.
43. [43] Huang, R., Xu, Y., Wan, W., Shou, X., Qian, J., You, Z., Liu, B., Chang, C., Zhou, T., Lippincott-Schwartz, J., Liu, W., Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol. Cell 57 (2015), 456–466.
44. [44] Rodgers, J.T., Lerin, C., Haas, W., Gygi, S.P., Spiegelman, B.M., Puigserver, P., Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434 (2005), 113–118.
45. [45] Rodgers, J.T., Puigserver, P., Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 12861–12866.
46. [46] Hallows, W.C., Yu, W., Denu, J.M., Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J. Biol. Chem. 287 (2012), 3850–3858.
47. [47] Lan, F., Cacicedo, J.M., Ruderman, N., Ido, Y., SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283 (2008), 27628–27635.
48. [48] Chang, C., Su, H., Zhang, D., Wang, Y., Shen, Q., Liu, B., Huang, R., Zhou, T., Peng, C., Wong, C.C.L., Shen, H.-M., Lippincott-Schwartz, J., Liu, W., AMPK-dependent phosphorylation of GAPDH triggers Sirt1 activation and is necessary for autophagy upon glucose starvation. Mol. Cell 60 (2015), 930–940.
49. [49] Cantó, C., Gerhart-Hines, Z., Feige, J.N., Lagouge, M., Noriega, L., Milne, J.C., Elliott, P.J., Puigserver, P., Auwerx, J., AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity. Nature 458 (2009), 1056–1060.
50. [50] Santolla, M.F., Avino, S., Pellegrino, M., De Francesco, E.M., De Marco, P., Lappano, R., Vivacqua, A., Cirillo, F., Rigiracciolo, D.C., Scarpelli, A., Abonante, S., Maggiolini, M., SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer. Cell Death Dis., 6, 2015, e1834.
51. [51] Jeon, S.-M., Chandel, N.S., Hay, N., AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485 (2012), 661–665.
52. [52] Asaka, R., Miyamoto, T., Yamada, Y., Ando, H., Mvunta, D.H., Kobara, H., Shiozawa, T., Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target. Lab. Investig. 95 (2015), 1363–1373.
53. [53] Azmi, A.S., Philip, P.A., Aboukameel, A., Wang, Z., Banerjee, S., Zafar, S.F., Goustin, A.-S., Almhanna, K., Yang, D., Sarkar, F.H., Mohammad, R.M., Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy. Curr. Cancer Drug Targets 10 (2010), 319–331.
54. [54] Martín-Montalvo, A., Villalba, J.M., Navas, P., de Cabo, R., NRF2, cancer and calorie restriction. Oncogene 30 (2011), 505–520.
55. [55] Motohashi, H., Yamamoto, M., Talalay, P., Hayes, J.D., McMahon, M., Rushmore, T.H., et al. Nrf2–Keap1 defines a physiologically important stress response mechanism. Trends Mol. Med. 10 (2004), 549–557.
56. [56] Pearson, K.J., Lewis, K.N., Price, N.L., Chang, J.W., Perez, E., Cascajo, M.V., Tamashiro, K.L., Poosala, S., Csiszar, A., Ungvari, Z., Kensler, T.W., Yamamoto, M., Egan, J.M., Longo, D.L., Ingram, D.K., Navas, P., de Cabo, R., Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 2325–2330.
57. [57] Knatko, E.V., Higgins, M., Fahey, J.W., Dinkova-Kostova, A.T., Loss of Nrf2 abrogates the protective effect of Keap1 downregulation in a preclinical model of cutaneous squamous cell carcinoma. Sci. Rep., 6, 2016, 25804.
58. [58] Menegon, S., Columbano, A., Giordano, S., Motohashi, H., Yamamoto, M., Ramos-Gomez, M., et al. The dual roles of Nrf2 in cancer. Trends Mol. Med. 22 (2016), 578–593.
59. [59] Chang, H.T., Olson, L.K., Schwartz, K.A., Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy. Nutr. Metab. (Lond.), 10, 2013, 47.
60. [60] Tisdale, M.J., Brennan, R.A., Loss of acetoacetate coenzyme A transferase activity in tumours of peripheral tissues. Br. J. Cancer 47 (1983), 293–297.
61. [61] Ganley, I.G., Lam, D.H., Wang, J., Ding, X., Chen, S., Jiang, X., ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284 (2009), 12297–12305.
62. [62] Puente, C., Hendrickson, R.C., Jiang, X., Nutrient-regulated phosphorylation of ATG13 inhibits starvation-induced autophagy. J. Biol. Chem. 291 (2016), 6026–6035.
63. [63] Jung, C.H., Jun, C.B., Ro, S.-H., Kim, Y.-M., Otto, N.M., Cao, J., Kundu, M., Kim, D.-H., ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20 (2009), 1992–2003.
64. [64] Fritzen, A.M., Frøsig, C., Jeppesen, J., Jensen, T.E., Lundsgaard, A.-M., Serup, A.K., Schjerling, P., Proud, C.G., Richter, E.A., Kiens, B., Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle. Cell. Signal. 28 (2016), 663–674.
65. [65] Cheong, H., Lindsten, T., Wu, J., Lu, C., Thompson, C.B., Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc. Natl. Acad. Sci. U. S. A. 108 (2011), 11121–11126.
66. [66] Yue, Z., Jin, S., Yang, C., Levine, A.J., Heintz, N., Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. U. S. A. 100 (2003), 15077–15082.
67. [67] Adams, O., Dislich, B., Berezowska, S., Schläfli, A.M., Seiler, C.A., Kroell, D., Tschan, M.P., Langer, R., Prognostic relevance of autophagy markers LC3B and p62 in esophageal adenocarcinomas. Oncotarget 7 (2016), 39241–39255.
68. [68] Tan, Q., Wang, M., Yu, M., Zhang, J., Bristow, R.G., Hill, R.P., Tannock, I.F., Role of autophagy as a survival mechanism for hypoxic cells in tumors. Neoplasia 18 (2016), 347–355.
69. [69] Piya, S., Kornblau, S.M., Ruvolo, V.R., Mu, H., Ruvolo, P.P., McQueen, T., Davis, R.E., Hail, N., Kantarjian, H., Andreeff, M., Borthakur, G., Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia. Blood 128 (2016), 1260–1269.
70. [70] Amaravadi, R.K., Lippincott-Schwartz, J., Yin, X.-M., Weiss, W.A., Takebe, N., Timmer, W., DiPaola, R.S., Lotze, M.T., White, E., Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res. 17 (2011), 654–666.
71. [71] Commisso, C., Davidson, S.M., Soydaner-Azeloglu, R.G., Parker, S.J., Kamphorst, J.J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J.A., Thompson, C.B., Rabinowitz, J.D., Metallo, C.M., Vander Heiden, M.G., Bar-Sagi, D., Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497 (2013), 633–637.
72. [72] Weiss, E.P., Fontana, L., Caloric restriction: powerful protection for the aging heart and vasculature. Am. J. Physiol. Heart Circ. Physiol. 301 (2011), 1205–1219.
73. [73] Tu, Y.-F., Lu, P.-J., Huang, C.-C., Ho, C.-J., Chou, Y.-P., Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain. Stroke 43 (2012), 491–498.
74. [74] Kincaid, B., Bossy-Wetzel, E., Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front. Aging Neurosci. 5 (2013), 1–13.
75. [75] Kim, J.-H., Lee, Y., Kwak, H.-B., Lawler, J.M., Lifelong wheel running exercise and mild caloric restriction attenuate nuclear EndoG in the aging plantaris muscle. Exp. Gerontol. 69 (2015), 122–128.
76. [76] Maiuri, M.C., Criollo, A., Tasdemir, E., Vicencio, J.M., Tajeddine, N., Hickman, J.A., Geneste, O., Kroemer, G., BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy 3 (2007), 374–376.
77. [77] Meynet, O., Zunino, B., Happo, L., Pradelli, L.A., Chiche, J., Jacquin, M.A., Mondragón, L., Tanti, J.-F., Taillan, B., Garnier, G., Reverso-Meinietti, J., Mounier, N., Michiels, J.-F., Michalak, E.M., Carles, M., Scott, C.L., Ricci, J.-E., Caloric restriction modulates Mcl-1 expression and sensitizes lymphomas to BH3 mimetic in mice. Blood 122 (2013), 2402–2411.
78. [78] Galet, C., Gray, A., Said, J.W., Castor, B., Wan, J., Beltran, P.J., Calzone, F.J., Elashoff, D., Cohen, P., Aronson, W.J., Effects of calorie restriction and IGF-1 receptor blockade on the progression of 22Rv1 prostate cancer xenografts. Int. J. Mol. Sci. 14 (2013), 13782–13795.
79. [79] Crabtree, H.G., Cramer, W., The action of radium on cancer cells. II.—Some factors determining the susceptibility of cancer cells to radium. Proc. R. Soc. B Biol. Sci. 113 (1933), 238–250.
80. [80] Tannenbaum, A., Silverstone, H., The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice. Cancer Res. 9 (1949), 724–727.
81. [81] Martinez-Outschoorn, U.E., Peiris-Pagés, M., Pestell, R.G., Sotgia, F., Lisanti, M.P., Cancer metabolism: a therapeutic perspective. Nat. Rev. Clin. Oncol., 2016, 10.1038/nrclinonc.2016.60.
82. [82] Chauvier, D., Lecoeur, H., Langonné, A., Borgne-Sanchez, A., Mariani, J., Martinou, J.-C., Rebouillat, D., Jacotot, E., Upstream control of apoptosis by caspase-2 in serum-deprived primary neurons. Apoptosis 10 (2005), 1243–1259.
83. [83] Li, D., Zhu, B., Ding, L., Lu, W., Xu, G., Wu, J., Role of the mitochondrial pathway in serum deprivation-induced apoptosis of rat endplate cells. Biochem. Biophys. Res. Commun. 452 (2014), 354–360.
84. [84] Shi, Y., Felley-Bosco, E., Marti, T.M., Orlowski, K., Pruschy, M., Stahel, R.A., Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin. BMC Cancer, 12, 2012, 571.
85. [85] Pirkmajer, S., Chibalin, A.V., Serum starvation: caveat emptor. Am. J. Phys. Cell Physiol. 301 (2011), C272–C279.
86. [86] Ferretti, A.C., Tonucci, F.M., Hidalgo, F., Almada, E., Larocca, M.C., Favre, C., AMPK and PKA interaction in the regulation of survival of liver cancer cells subjected to glucose starvation. Oncotarget 7:14 (2016), 17815–17828.
87. [87] Zhang, K., Kaufman, R.J., The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66 (2006), S102–S109.
88. [88] Marciniak, S.J., Yun, C.Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H.P., Ron, D., CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18 (2004), 3066–3077.
89. [89] Klement, R.J., Champ, C.E., Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation. Cancer Metastasis Rev. 33 (2014), 217–229.
90. [90] Champ, C.E., Baserga, R., Mishra, M.V., Jin, L., Sotgia, F., Lisanti, M.P., Pestell, R.G., Dicker, A.P., Simone, N.L., Nutrient restriction and radiation therapy for cancer treatment: when less is more. Oncologist 18 (2013), 97–103.
91. [91] Safdie, F.M., Dorff, T., Quinn, D., Fontana, L., Wei, M., Lee, C., Cohen, P., Longo, V.D., Fasting and cancer treatment in humans: a case series report. Aging (Albany NY) 1 (2009), 988–1007.
92. [92] Liu, Q., Liu, Z., Chen, H., Ma, L., Liu, L., Zhang, J., He, Y., Chen, J., Qian, Q., et al. Treatment with growth hormone, somatostatin, and insulin in combination with hypocaloric parenteral nutrition in gastrointestinal cancer patients after surgery. Nutrition 27 (2011), 633–640.
93. [93] Li, J.-H., Han, L., Du, T.-P., Guo, M.-J., The effect of low-nitrogen and low-calorie parenteral nutrition combined with enteral nutrition on inflammatory cytokines and immune functions in patients with gastric cancer: a double blind placebo trial. Eur. Rev. Med. Pharmacol. Sci. 19 (2015), 1345–1350.
94. [94] Saxton, J.M., Scott, E.J., Daley, A.J., Woodroofe, M., Mutrie, N., Crank, H., Powers, H.J., Coleman, R.E., Effects of an exercise and hypocaloric healthy eating intervention on indices of psychological health status, hypothalamic-pituitary-adrenal axis regulation and immune function after early-stage breast cancer: a randomised controlled trial. Breast Cancer Res., 16, 2014, R39.
95. [95] Scott, E., Daley, A.J., Doll, H., Woodroofe, N., Coleman, R.E., Mutrie, N., Crank, H., Powers, H.J., Saxton, J.M., Effects of an exercise and hypocaloric healthy eating program on biomarkers associated with long-term prognosis after early-stage breast cancer: a randomized controlled trial. Cancer Causes Control 24 (2013), 181–191.
96. [96] Fontana, L., Weiss, E.P., Villareal, D.T., Klein, S., Holloszy, J.O., Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 7 (2008), 681–687.
97. [97] Vidali, S., Aminzadeh, S., Lambert, B., Rutherford, T., Sperl, W., Kofler, B., Feichtinger, R.G., Mitochondria: the ketogenic diet—a metabolism-based therapy. Int. J. Biochem. Cell Biol. 63 (2015), 55–59.
98. [98] Schwartz, K., Chang, H.T., Nikolai, M., Pernicone, J., Rhee, S., Olson, K., Kurniali, P.C., Hord, N.G., Noel, M., Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab., 3, 2015, 3.
99. [99] Lee, C., Safdie, F.M., Raffaghello, L., Wei, M., Madia, F., Parrella, E., Hwang, D., Cohen, P., Bianchi, G., Longo, V.D., Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 70 (2010), 1564–1572.
100. [100] Klaassen, C.D., Slitt, A.L., Regulation of hepatic transporters by xenobiotic receptors. Curr. Drug Metab. 6 (2005), 309–328.
101. [101] Kensler, T.W., He, X., Otieno, M., Egner, P.A., Jacobson, L.P., Chen, B., Wang, J.S., Zhu, Y.R., Zhang, B.C., Wang, J.B., Wu, Y., Zhang, Q.N., Qian, G.S., Kuang, S.Y., Fang, X., Li, Y.F., Yu, L.Y., Prochaska, H.J., Davidson, N.E., Gordon, G.B., Gorman, M.B., Zarba, A., Enger, C., Muñoz, A., Helzlsouer, K.J., Oltipraz chemoprevention trial in Qidong, People's Republic of China: modulation of serum aflatoxin albumin adduct biomarkers. Cancer Epidemiol. Biomark. Prev. 7 (1998), 127–134.
102. [102] Christadoss, P., Talal, N., Lindstrom, J., Fernandes, G., Suppression of cellular and humoral immunity to T-dependent antigens by calorie restriction. Cell. Immunol. 88 (1984), 1–8.
103. [103] Taylor, A.K., Cao, W., Vora, K.P., De La Cruz, J., Shieh, W.-J., Zaki, S.R., Katz, J.M., Sambhara, S., Gangappa, S., Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J. Infect. Dis. 207 (2013), 501–510.
104. [104] Howard, J.K., Lord, G.M., Matarese, G., Vendetti, S., Ghatei, M.A., Ritter, M.A., Lechler, R.I., Bloom, S.R., Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104 (1999), 1051–1059.
105. [105] González-Torres, C., González-Martínez, H., Miliar, A., Nájera, O., Graniel, J., Firo, V., Alvarez, C., Bonilla, E., Rodríguez, L., Effect of malnutrition on the expression of cytokines involved in Th1 cell differentiation. Nutrients. 5 (2013), 579–593.
106. [106] Iyer, S.S., Chatraw, J.H., Tan, W.G., Wherry, E.J., Becker, T.C., Ahmed, R., Kapasi, Z.F., Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells. J. Immunol. 188 (2012), 77–84.
107. [107] Rytter, M.J.H., Kolte, L., Briend, A., Friis, H., Christensen, V.B., The immune system in children with malnutrition—a systematic review. PLoS One, 9, 2014, e105017, 10.1371/journal.pone.0105017.
108. [108] He, Z.X., Sun, Z.H., Yang, W.Z., Beauchemin, K.A., Tang, S.X., Zhou, C.S., Han, X.F., Wang, M., Kang, J.H., Tan, Z.L., Effects of maternal protein or energy restriction during late gestation on immune status and responses to lipopolysaccharide challenge in postnatal young goats. J. Anim. Sci. 92 (2014), 4856–4864, 10.2527/jas.2014-7904.
109. [109] Di Biase, S., Lee, C., Brandhorst, S., Manes, B., Buono, R., Cheng, C.-W., Cacciottolo, M., Martin-Montalvo, A., de Cabo, R., Wei, M., Morgan, T.E., Longo, V.D., et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30 (2016), 136–146.
110. [110] Pietrocola, F., Pol, J., Vacchelli, E., Rao, S., Enot, D.P., Baracco, E.E., Levesque, S., Castoldi, F., Jacquelot, N., Yamazaki, T., Senovilla, L., Marino, G., Aranda, F., Durand, S., Sica, V., Chery, A., Lachkar, S., Sigl, V., Bloy, N., Buque, A., Falzoni, S., Ryffel, B., Apetoh, L., Di Virgilio, F., Madeo, F., Maiuri, M.C., Zitvogel, L., Levine, B., Penninger, J.M., Kroemer, G., Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30 (2016), 147–160.
111. [111] Senichkin, V.V., Kopeina, G.S., Zamaraev, A.V., Lavrik, I.N., Zhivotovsky, B.D., Nutrient restriction in combinatory therapy of tumors. Mol. Biol. 50 (2016), 362–378.
112. [112] Madeo, F., Pietrocola, F., Eisenberg, T., Kroemer, G., Caloric restriction mimetics: towards a molecular definition. Nat. Rev. Drug Discov. 13 (2014), 727–740.
113. [113] Lane MA, R.G., Ingram, D.K., 2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction. J. Anti. Aging. Med. 1 (1998), 327–337.
114. [114] Dwarakanath, B., Jain, V., Targeting glucose metabolism with 2-deoxy-D-glucose for improving cancer therapy. Future Oncol. 5 (2009), 581–585.
115. [115] Raez, L.E., Papadopoulos, K., Ricart, A.D., Chiorean, E.G., DiPaola, R.S., Stein, M.N., Rocha Lima, C.M., Schlesselman, J.J., Tolba, K., Langmuir, V.K., Kroll, S., Jung, D.T., Kurtoglu, M., Rosenblatt, J., Lampidis, T.J., A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 71 (2013), 523–530.
116. [116] Vijayaraghavan, R., Kumar, D., Dube, S.N., Singh, R., Pandey, K.S., Bag, B.C., Kaushik, M.P., Sekhar, K., Dwarakanath, B.S., Ravindranath, T., Acute toxicity and cardio-respiratory effects of 2-deoxy-D-glucose: a promising radio sensitiser. Biomed. Environ. Sci. 19 (2006), 96–103.
117. 18F-FDG PET imaging in response assessment and restaging after definitive treatment of Merkel cell carcinoma. J. Nucl. Med. 56 (2015), 1328–1333.
118. 18F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open-label randomised controlled trial. Lancet Oncol. 17 (2016), 193–199.
119. [119] Coudert, B., Pierga, J.-Y., Mouret-Reynier, M.-A., Kerrou, K., Ferrero, J.-M., Petit, T., Kerbrat, P., Dupré, P.-F., Bachelot, T., Gabelle, P., Giard, S., Coeffic, D., Bougnoux, P., Prevost, J.-B., Paintaud, G., Thibault, G., Hernandez, J., Coudert, M., Arnould, L., Berriolo-Riedinger, A., Use of [(18)F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [(18)F]-FDG PET-predicted non-responders (AVATAXHER). Lancet Oncol. 15 (2014), 1493–1502.
120. 18F-FDG PET is an early predictor of overall survival in suspected atypical parkinsonism. J. Nucl. Med. 56 (2015), 1541–1546.
121. 18F-FDG-PET. Nucl. Med. Commun., 1, 2015.
122. [122] Libby, G., Donnelly, L.A., Donnan, P.T., Alessi, D.R., Morris, A.D., Evans, J.M.M., New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32 (2009), 1620–1625.
123. [123] Wu, L., Zhu, J., Prokop, L.J., Murad, M.H., Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies. Sci. Rep., 5, 2015, 10147, 10.1038/srep10147.
124. [124] Miranda, V.C., Braghiroli, M.I., Faria, L.D., Bariani, G., Alex, A., Bezerra Neto, J.E., Capareli, F.C., Sabbaga, J., Ying, H., et al. Phase 2 trial of metformin combined with 5-fluorouracil in patients with refractory metastatic colorectal cancer. Clin. Colorectal Cancer, 2016, 623–640.
125. [125] de Beer, J.C., Liebenberg, L., Does cancer risk increase with HbA1c, independent of diabetes?. Br. J. Cancer 110 (2014), 2361–2368.
126. [126] Sivalingam, V.N., Kitson, S., McVey, R., Roberts, C., Pemberton, P., Gilmour, K., Ali, S., Renehan, A.G., Kitchener, H.C., Crosbie, E.J., Measuring the biological effect of presurgical metformin treatment in endometrial cancer. Br. J. Cancer 114 (2016), 281–289.
127. [127] Howells, L.M., Berry, D.P., Elliott, P.J., Jacobson, E.W., Hoffmann, E., Hegarty, B., Brown, K., Steward, W.P., Gescher, A.J., Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev. Res. (Phila.) 4 (2011), 1419–1425.
128. [128] Patel, K.R., Brown, V.A., Jones, D.J.L., Britton, R.G., Hemingway, D., Miller, A.S., West, K.P., Booth, T.D., Perloff, M., Crowell, J.A., Brenner, D.E., Spiller, R., et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 70 (2010), 7392–7399.
129. [129] Chow, H.-H.S., Garland, L.L., Heckman-Stoddard, B.M., Hsu, C.-H., Butler, V.D., Cordova, C.A., Chew, W.M., Cornelison, T.L., A pilot clinical study of resveratrol in postmenopausal women with high body mass index: effects on systemic sex steroid hormones. J. Transl. Med., 12, 2014, 223.
130. [130] Zhu, W., Qin, W., Zhang, K., Rottinghaus, G.E., Chen, Y.-C., Kliethermes, B., Sauter, E.R., Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr. Cancer 64 (2012), 393–400.
131. [131] James, M.I., Iwuji, C., Irving, G., Karmokar, A., Higgins, J.A., Griffin-Teal, N., Thomas, A., Greaves, P., Cai, H., Patel, S.R., Morgan, B., Dennison, A., Metcalfe, M., Garcea, G., Lloyd, D.M., Berry, D.P., Steward, W.P., Howells, L.M., Brown, K., Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Lett. 364 (2015), 135–141.
132. [132] Bayet-Robert, M., Kwiatkowski, F., Leheurteur, M., Gachon, F., Planchat, E., Abrial, C., Mouret-Reynier, M.-A., Durando, X., Barthomeuf, C., Chollet, P., Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol. Ther. 9 (2010), 8–14.
133. [133] 2007 - FDA Approves New Drug for Advanced Kidney Cancer, (n.d.). http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108924.htm (accessed 25 July 2016).
134. [134] Hess, G., Keller, U., Scholz, C.W., Witzens-Harig, M., Atta, J., Buske, C., Kirschey, S., Ruckes, C., Medler, C., van Oordt, C., Klapper, W., Theobald, M., Dreyling, M., Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma. Leukemia 29 (2015), 1695–1701.
135. [135] Hobday, T.J., Qin, R., Reidy-Lagunes, D., Moore, M.J., Strosberg, J., Kaubisch, A., Shah, M., Kindler, H.L., Lenz, H.-J., Chen, H., Erlichman, C., Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J. Clin. Oncol. 33 (2015), 1551–1556.
136. [136] Eroglu, Z., Tawbi, H.A., Hu, J., Guan, M., Frankel, P.H., Ruel, N.H., Wilczynski, S., Christensen, S., Gandara, D.R., Chow, W.A., A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. Br. J. Cancer 112 (2015), 1644–1651.
137. [137] Fenske, T.S., Shah, N.M., Kim, K.M., Saha, S., Zhang, C., Baim, A.E., Farnen, J.P., Onitilo, A.A., Blank, J.H., Ahuja, H., Wassenaar, T., Qamar, R., Mansky, P., Traynor, A.M., Mattison, R.J., Kahl, B.S., A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: a Wisconsin Oncology Network study. Cancer 121 (2015), 3465–3471.
138. [138] Knox, J.J., Qin, R., Strosberg, J.R., Tan, B., Kaubisch, A., El-Khoueiry, A.B., Bekaii-Saab, T.S., Rousey, S.R., Chen, H.X., Erlichman, C., A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma. Investig. New Drugs 33 (2015), 241–246.
139. [139] Fouladi, M., Perentesis, J.P., Wagner, L.M., Vinks, A.A., Reid, J.M., Ahern, C., Thomas, G., Mercer, C.A., Krueger, D.A., Houghton, P.J., Doyle, L.A., Chen, H., Weigel, B., Blaney, S.M., A phase I study of cixutumumab (IMC-A12) in combination with temsirolimus (CCI-779) in children with recurrent solid tumors: a Children's Oncology Group phase I consortium report. Clin. Cancer Res. 21 (2015), 1558–1565.
140. [140] Pazdur, R., FDA Approval for Everolimus. https://www.cancer.gov/about-cancer/treatment/drugs/fda-everolimus, 2013.
141. [141] Chow, H., Ghosh, P.M., de Vere White, R., Evans, C.P., Dall'Era, M.A., Yap, S.A., Li, Y., Beckett, L.A., Lara, P.N., Pan, C.-X., A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer. Cancer 122 (2016), 1897–1904.
142. [142] Yao, J.C., Fazio, N., Singh, S., Buzzoni, R., Carnaghi, C., Wolin, E., Chen, H., et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387 (2016), 968–977.
143. [143] Di Cosimo, S., Sathyanarayanan, S., Bendell, J.C., Cervantes, A., Stein, M.N., Braña, I., Roda, D., Haines, B.B., Zhang, T., Winter, C.G., Jha, S., Xu, Y., Frazier, J., Klinghoffer, R.A., Leighton-Swayze, A., Song, Y., Ebbinghaus, S., Baselga, J., Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial. Clin. Cancer Res. 21 (2015), 49–59.
144. [144] Zibelman, M., Wong, Y.-N., Devarajan, K., Malizzia, L., Corrigan, A., Olszanski, A.J., Denlinger, C.S., Roethke, S.K., Tetzlaff, C.H., Plimack, E.R., Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors. Investig. New Drugs 33 (2015), 1040–1047.
145. [145] Sivendran, S., Agarwal, N., Gartrell, B., Ying, J., Douketis, J., et al. Metabolic complications with the use of mTOR inhibitors for cancer therapy. Cancer Treat. Rev. 40 (2014), 190–196.
146. [146] Caffa, I., D'Agostino, V., Damonte, P., Soncini, D., Cea, M., Monacelli, F., Odetti, P., Ballestrero, A., Provenzani, A., Longo, V.D., Nencioni, A., Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget 6 (2015), 11820–11832.
147. [147] Zhijun, H., Shusheng, W., Han, M., Jianping, L., Li-Sen, Q., Dechun, L., Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells. Tumour Biol. 37 (2016), 10257–10267.
148. [148] Rieger, J., Bähr, O., Maurer, G.D., Hattingen, E., Franz, K., Brucker, D., Walenta, S., Kämmerer, U., Coy, J.F., Weller, M., Steinbach, J.P., ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int. J. Oncol. 44 (2014), 1843–1852.
149. [149] Peng, M., Huang, Y., Tao, T., Peng, C.-Y., Su, Q., Xu, W., Darko, K.O., Tao, X., Yang, X., Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk. Sci. Rep., 6, 2016, 28611.
150. [150] Chen, H., Yao, W., Chu, Q., Han, R., Wang, Y., Sun, J., Wang, D., Wang, Y., Cao, M., Song, Y., et al. Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes. Cancer Lett. 369 (2015), 97–102.
151. [151] Saba, N.F., Hurwitz, S.J., Magliocca, K., Kim, S., Owonikoko, T.K., Harvey, D., Ramalingam, S.S., Chen, Z., Rogerio, J., Mendel, J., Kono, S.A., Lewis, C., Chen, A.Y., Higgins, K., El-Deiry, M., Wadsworth, T., Beitler, J.J., Shin, D.M., Sun, S.-Y., Khuri, F.R., Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck. Cancer 120 (2014), 3940–3951.
152. [152] Shih, K.C., Chowdhary, S., Rosenblatt, P., Weir, A.B., Shepard, G.C., Williams, J.T., Shastry, M., Burris, H.A., Hainsworth, J.D., A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma. J. Neuro-Oncol. 129 (2016), 281–288.
153. [153] Geiger, J.L., Bauman, J.E., Gibson, M.K., Gooding, W.E., Varadarajan, P., Kotsakis, A., Martin, D., Gutkind, J., Hedberg, M.L., Grandis, J.R., Argiris, A., Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. Head Neck 38 (2016), 1759–1764.
154. [154] Motzer, R.J., Alyasova, A., Ye, D., Karpenko, A., Li, H., Alekseev, B., Xie, L., Kurteva, G., Kowalyszyn, R., Karyakin, O.n., Neron, Y., Cosgriff, T., Collins, L., Brechenmacher, T., Lin, C., Morgan, L., Yang, L., Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann. Oncol. 27 (2016), 441–448.
155. [155] Hurvitz, S.A., Dalenc, F., Campone, M., O'Regan, R.M., Tjan-Heijnen, V.C., Gligorov, J., nLlombart, A., Jhangiani, H., Mirshahidi, H.R., Tan-Chiu, E., Miao, S., El-Hashimy, M., Lincy, J., Taran, T., Soria, J.-C., Sahmoud, T., André, F., A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res. Treat. 141 (2013), 437–446.
156. [156] Dreyling, M., Jurczak, W., Jerkeman, M., Silva, R.S., Rusconi, C., Trneny, M., Offner, F., Caballero, D., et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 387 (2016), 770–778.
157. [157] Piha-Paul, S.A., Munster, P.N., Hollebecque, A., Argilés, G., Dajani, O., Cheng, J.D., Wang, R., Swift, A., et al. Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours. Eur. J. Cancer 51 (2015), 1865–1873.
158. [158] Oza, A.M., Pignata, S., Poveda, A., McCormack, M., Clamp, A., Schwartz, B., Cheng, J., Li, X., Campbell, K., Dodion, P., Haluska, F.G., Randomized Phase II Trial of Ridaforolimus in Advanced Endometrial Carcinoma. J. Clin. Oncol. 33 (2015), 3576–3582.
159. [159] Seiler, M., Ray-Coquard, I., Melichar, B., Yardley, D.A., Wang, R.X., Dodion, P.F., Lee, M.A., Barros, F.F., et al. Oral ridaforolimus plus trastuzumab for patients with HER2 + trastuzumab-refractory metastatic breast cancer. Clin. Breast Cancer 15 (2015), 60–65.
160. [160] Higurashi, T., Hosono, K., Takahashi, H., Komiya, Y., Umezawa, S., Sakai, E., Uchiyama, T., Taniguchi, L., Levin, T., et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 17 (2016), 475–483.
161. [161] Sayed, R., Saad, A.S., El Wakeel, L., Elkholy, E., Badary, O., Metformin Addition to Chemotherapy in Stage IV Non-Small Cell Lung Cancer: an Open Label Randomized Controlled Study. Asian Pac. J. Cancer Prev. 16 (2015), 6621–6626.
162. [162] Ko, K.-P., Ma, S.H., Yang, J.-J., Hwang, Y., Ahn, C., Cho, Y.-M., Noh, D.-Y., Park, B.-J., Han, W., Park, S.K., Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial. Breast Cancer Res. Treat. 153 (2015), 361–370.
163. [163] Kordes, S., Pollak, M.N., Zwinderman, A.H., Mathôt, R.A., Weterman, M.J., Beeker, A., Punt, C.J., Richel, D.J., Kroemer, G., et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 16 (2015), 839–847.
164. [164] Goodwin, P.J., Parulekar, W.R., Gelmon, K.A., Shepherd, L.E., Ligibel, J.A., Hershman, D.L., Rastogi, P., Mayer, I.A., Hobday, T.J., Lemieux, J., Thompson, A.M., Pritchard, K.I., Whelan, T.J., Mukherjee, S.D., Chalchal, H.I., Oja, C.D., Tonkin, K.S., Bernstein, V., Chen, B.E., Stambolic, V., Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J. Natl. Cancer Inst. 4 (2015), 107–113.
165. [165] Mahammedi, H., Planchat, E., Pouget, M., Durando, X., Curé, H., Guy, L., Van-Praagh, I., Savareux, L., Atger, M., Bayet-Robert, M., Gadea, E., Abrial, C., Thivat, E., Chollet, P., Eymard, J.-C.m., The New Combination Docetaxel, Prednisone and Curcumin in Patients with Castration-Resistant Prostate Cancer: A Pilot Phase II Study. Oncology 90 (2016), 69–78.
166. [166] Panahi, Y., Saadat, A., Beiraghdar, F., Sahebkar, A., Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial. Phytother. Res. 28 (2014), 1461–1467.