Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

  • Tan, Heng Kean (Malaysian Institute of Pharmaceuticals and Nutraceuticals, Ministry of Science, Technology and Innovation (MOSTI)) ;
  • Moad, Ahmed Ismail Hassan (Advanced Medical and Dental Institute, Universiti Sains Malaysia) ;
  • Tan, Mei Lan (Malaysian Institute of Pharmaceuticals and Nutraceuticals, Ministry of Science, Technology and Innovation (MOSTI))
  • Published : 2014.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.

Keywords

References

  1. Abdulkareem IH, Blair M (2013). Phosphatase and tensin homologue deleted on chromosome 10. Niger Med J, 54, 79-86. https://doi.org/10.4103/0300-1652.110033
  2. Abraham RT (1998). Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signalling. Curr Opin Immunol, 10, 330-6. https://doi.org/10.1016/S0952-7915(98)80172-6
  3. Aggarwal BB, Bhardwaj A, Aggarwal RS, et al (2004). Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res, 24, 2783-840.
  4. Anastasius N, Boston S, Lacey M, Storing N, Whitehead SA (2009). Evidence that low-dose, long-term genistein treatment inhibits oestradiol-stimulated growth in MCF-7 cells by down-regulation of the PI3-kinase/Akt signalling pathway. J Steroid Biochem Mol Biol, 116, 50-5. https://doi.org/10.1016/j.jsbmb.2009.04.009
  5. Aoki H, Takada Y, Kondo S, et al (2007). Evidence that curcumin suppresses the growth of malignant gliomas In vitro and In vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signalling pathways. Mol Pharmacol, 72, 29-39. https://doi.org/10.1124/mol.106.033167
  6. Asnaghi L, Bruno P, Priulla M, et al (2004). mTOR: a protein kinase switching between life and death. Pharmacol Res 50, 545-9. https://doi.org/10.1016/j.phrs.2004.03.007
  7. Aziz MH, Nihal M, Fu VX, et al (2006). Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/ Akt pathway and Bcl-2 family proteins. Mol Cancer Ther 5, 1335-41. https://doi.org/10.1158/1535-7163.MCT-05-0526
  8. Ballou LM, Lin RZ (2008). Rapamycin and mTOR kinase inhibitors. J Chem Biol, 1, 27-36. https://doi.org/10.1007/s12154-008-0003-5
  9. Banerjee S, Zhang Y, Wang Z, et al (2007). In vitro and In vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int J Cancer, 120, 906-17. https://doi.org/10.1002/ijc.22332
  10. Baselga J (2011). Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist, 16, 12-9.
  11. Beevers CS, Chen L, Liu L, et al (2009). Curcumin disrupts the mammalian target of rapamycin-raptor complex. Cancer Res, 69, 1000-8. https://doi.org/10.1158/0008-5472.CAN-08-2367
  12. Beevers CS, Li F, Liu L, et al (2006). Curcumin inhibits the mammalian target of rapamycin-mediated signalling pathways in cancer cells. Int J Cancer, 119, 757-64. https://doi.org/10.1002/ijc.21932
  13. Bharti AC, Aggarwal BB (2002). Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol, 64, 883-8. https://doi.org/10.1016/S0006-2952(02)01154-1
  14. Brito PM, Devillard R, Negre-Salvayre A, et al (2009). Resveratrol inhibits the mTOR mitogenic signalling evoked by oxidized LDL in smooth muscle cells. Atherosclerosis 205, 126-34. https://doi.org/10.1016/j.atherosclerosis.2008.11.011
  15. Brown VA, Patel KR, Viskaduraki M, et al (2010). Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res, 70, 9003-11. https://doi.org/10.1158/0008-5472.CAN-10-2364
  16. Caron E, Ghosh S, Matsuoka Y, et al (2010). A comprehensive map of the mTOR signalling network. Mol Syst Biol, 6, 453.
  17. Carroll RE, Benya RV, Turgeon DK, et al (2011). Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res, 4, 354-64. https://doi.org/10.1158/1940-6207.CAPR-10-0098
  18. Chan S (2004). Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer 91, 1420-4. https://doi.org/10.1038/sj.bjc.6602162
  19. Chen HX, Sharon E (2013). IGF-1R as an anti-cancer target-- trials and tribulations. Chin J Cancer, 32, 242-52. https://doi.org/10.5732/cjc.012.10263
  20. Cheng AL, Hsu CH, Lin JK, et al (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with highrisk or pre-malignant lesions. Anticancer Res, 21, 2895-900.
  21. Chiang CT, Way TD, Tsai SJ, et al (2007). Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation. FEBS Lett, 581, 5735-42. https://doi.org/10.1016/j.febslet.2007.11.021
  22. Chow HH, Garland LL, Hsu CH, et al (2010). Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res, 3, 1168-75. https://doi.org/10.1158/1940-6207.CAPR-09-0155
  23. Chu Y-F, Sun J, Wu X, et al (2002). Antioxidant and antiproliferative activities of common vegetables. J Agr Food Chem, 50, 6910-6. https://doi.org/10.1021/jf020665f
  24. Cragg GM, Newman DJ, Snader KM (1997). Natural products in drug discovery and development. J Nat Prod, 60, 52-60. https://doi.org/10.1021/np9604893
  25. da Rocha AB, Lopes RM, Schwartsmann G (2001). Natural products in anticancer therapy. Curr Opin Pharmacol, 1, 364-9. https://doi.org/10.1016/S1471-4892(01)00063-7
  26. Dalessandri KM, Firestone GL, Fitch MD, et al (2004). Pilot study: effect of 3,3'-Diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer, 50, 161-7. https://doi.org/10.1207/s15327914nc5002_5
  27. Das A, Banik NL, Ray SK (2010). Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes. Cancer, 116, 164-76.
  28. Dhillon N, Aggarwal BB, Newman RA, et al (2008). Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res, 14, 4491-9. https://doi.org/10.1158/1078-0432.CCR-08-0024
  29. Dowling RJ, Topisirovic I, Fonseca BD, et al (2010). Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta, 1804, 433-9. https://doi.org/10.1016/j.bbapap.2009.12.001
  30. Faria A, Calhau C (2010). Chapter 36 - Pomegranate in human health: an overview (W. Ronald Ross and R. P. Victor, Ed.^ Eds). Academic Press, San Diego, pp. 551-63.
  31. Faried A, Kurnia D, Faried LS, et al (2007). Anticancer effects of gallic acid isolated from Indonesian herbal medicine, Phaleria macrocarpa (Scheff.) Boerl, on human cancer cell lines. Int J Oncol, 30, 605-13.
  32. Fingar DC, Richardson CJ, Tee AR, et al (2004). mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol, 24, 200-16. https://doi.org/10.1128/MCB.24.1.200-216.2004
  33. Fruman DA, Rommel C (2014). PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov, 13, 140-56. https://doi.org/10.1038/nrd4204
  34. Galluzzi L, Vicencio JM, Kepp O, et al (2008). To die or not to die: that is the autophagic question. Curr Mol Med, 8, 78-91. https://doi.org/10.2174/156652408783769616
  35. Ganley IG, Lam du H, Wang J, et al (2009). ULK1.ATG13. FIP200 complex mediates mTOR signalling and is essential for autophagy. J Biol Chem, 284, 12297-305. https://doi.org/10.1074/jbc.M900573200
  36. Garcia-Echeverria C (2010). Allosteric and ATP-competitive kinase inhibitors of mTOR for cancer treatment. Bioorg Med Chem Lett, 20, 4308-12. https://doi.org/10.1016/j.bmcl.2010.05.099
  37. Garikapaty VP, Ashok BT, Tadi K, et al (2006). 3,3'-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer. Biochem Biophys Res Commun, 340, 718-25. https://doi.org/10.1016/j.bbrc.2005.12.059
  38. Gera JF, Mellinghoff IK, Shi Y, et al (2004). AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem, 279, 2737-46. https://doi.org/10.1074/jbc.M309999200
  39. Ghayad SE, Cohen PA (2010). Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. Recent Pat Anticancer Drug Discov, 5, 29-57. https://doi.org/10.2174/157489210789702208
  40. Gomez-Pinillos A, Ferrari AC (2012). mTOR signalling pathway and mTOR inhibitors in cancer therapy. Hematol Oncol Clin North Am, 26, 483-505. https://doi.org/10.1016/j.hoc.2012.02.014
  41. Guertin DA, Kim D-H, Sabatini DM (2004). Growth control through the mTOR network. In 'Cell Growth: Control of Cell Size' (Hall MN et al., eds), Cold Spring Harbor Laboratory Press, pp. 193-234.
  42. Guertin DA, Sabatini DM (2009). The pharmacology of mTOR inhibition. Sci Signal, 2, 24.
  43. Gullett NP, Ruhul Amin AR, Bayraktar S, et al (2010). Cancer prevention with natural compounds. Semin Oncol, 37, 258-81. https://doi.org/10.1053/j.seminoncol.2010.06.014
  44. Han D, Li SJ, Zhu YT, et al (2013). LKB1/AMPK/mTOR signalling pathway in non-small-cell lung cancer. Asian Pac J Cancer Prev, 14, 4033-9. https://doi.org/10.7314/APJCP.2013.14.7.4033
  45. Hardwick JS, Kuruvilla FG, Tong JK, et al (1999). Rapamycinmodulated transcription defines the subset of nutrientsensitive signalling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci USA, 96, 14866-70. https://doi.org/10.1073/pnas.96.26.14866
  46. Hasskarl J (2014). Everolimus. Recent Results Cancer Res, 201, 373-92. https://doi.org/10.1007/978-3-642-54490-3_23
  47. Hay N, Sonenberg N (2004). Upstream and downstream of mTOR. Genes Dev, 18, 1926-45. https://doi.org/10.1101/gad.1212704
  48. He X, Wang Y, Zhu J, et al (2010). Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signalling. Cancer Lett, 28, 168-76
  49. He Y, Li D, Cook SL, et al (2013). Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol Biol Cell, 24, 3369-80. https://doi.org/10.1091/mbc.E13-07-0405
  50. Heath EI, Heilbrun LK, Li J, et al (2010). A Phase I doseescalation study of oral BR-DIM (BioResponse 3,3'- Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res, 2, 402-11.
  51. Hidalgo M, Rowinsky EK (2000). The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene, 19, 6680-6. https://doi.org/10.1038/sj.onc.1204091
  52. Hosokawa N, Sasaki T, Iemura S, et al (2009). Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy, 5, 973-9. https://doi.org/10.4161/auto.5.7.9296
  53. Houghton PJ (2010). mTOR and Cancer Therapy: General Principles (V. A. Polunovsky and P. J. Houghton, Ed.^ Eds.), pp. 113-31. Humana Press, Springer New York Dordrecht Heidelberg London.
  54. Howells LM, Berry DP, Elliott PJ, et al (2011). Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases-- safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res, 4, 1419-25. https://doi.org/10.1158/1940-6207.CAPR-11-0148
  55. Hsieh TC, Wu JM (2009). Targeting CWR22Rv1 prostate cancer cell proliferation and gene expression by combinations of the phytochemicals EGCG, genistein and quercetin. Anticancer Res, 29, 4025-32.
  56. Huang CH, Tsai SJ, Wang YJ, et al (2009). EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Mol Nutr Food Res, 53, 1156-65. https://doi.org/10.1002/mnfr.200800592
  57. Huang S, Houghton PJ (2003). Targeting mTOR signalling for cancer therapy. Curr Opin Pharmacol, 3, 371-7. https://doi.org/10.1016/S1471-4892(03)00071-7
  58. Hwang YW, Kim SY, Jee SH, et al (2009). Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutr Cancer, 61, 598-606. https://doi.org/10.1080/01635580902825639
  59. Inoki K, Li Y, Zhu T, et al (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol, 4, 648-57. https://doi.org/10.1038/ncb839
  60. Irving GR, Howells LM, Sale S, et al (2013). Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration--a clinical pilot study including assessment of patient acceptability. Cancer Prev Res (Phila), 6, 119-28. https://doi.org/10.1158/1940-6207.CAPR-12-0281
  61. Jacinto E, Loewith R, Schmidt A, et al (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol, 6, 1122-8. https://doi.org/10.1038/ncb1183
  62. Jiang H, Shang X, Wu H, et al (2009). Resveratrol downregulates PI3K/Akt/mTOR signalling pathways in human U251 glioma cells. J Exp Ther Oncol, 8, 25-33.
  63. Johnson SM, Gulhati P, Arrieta I, et al (2009). Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/ mTOR signalling. Anticancer Res, 29, 3185-90.
  64. Jung CH, Jun CB, Ro SH, et al (2009). ULK-Atg13-FIP200 complexes mediate mTOR signalling to the autophagy machinery. Mol Biol Cell, 20, 1992-2003. https://doi.org/10.1091/mbc.E08-12-1249
  65. Kadowaki M, Kanazawa T (2003). Amino acids as regulators of proteolysis. J Nutr, 133, 2052-6.
  66. Kanai M, Otsuka Y, Otsuka K, et al (2013). A Phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients. Cancer Chemother Pharmacol, 71, 1521-30. https://doi.org/10.1007/s00280-013-2151-8
  67. Kanai M, Yoshimura K, Asada M, et al (2011). A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol, 68, 157-64. https://doi.org/10.1007/s00280-010-1470-2
  68. Kang Y-J, Chung H-J, Nam J-W, et al (2011). Cytotoxic and antineoplastic activity of timosaponin a-iii for human colon cancer cells. J Nat Prod, 74, 701-6. https://doi.org/10.1021/np1007735
  69. Katiyar S, Elmets CA, Katiyar SK (2007). Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. J Nutr Biochem, 18, 287-96. https://doi.org/10.1016/j.jnutbio.2006.08.004
  70. Khan N, Afaq F, Kweon MH, et al (2007a). Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. Cancer Res, 67, 3475-82. https://doi.org/10.1158/0008-5472.CAN-06-3941
  71. Khan N, Hadi N, Afaq F, et al (2007b). Pomegranate fruit extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice. Carcinogenesis, 28, 163-73. https://doi.org/10.1093/carcin/bgl145
  72. Kim DH, Sarbassov DD, Ali SM, et al (2002a). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110, 163-75. https://doi.org/10.1016/S0092-8674(02)00808-5
  73. Kim ND, Mehta R, Yu W, et al (2002b). Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res Treat, 71, 203-17. https://doi.org/10.1023/A:1014405730585
  74. Kim SH, Kim YB, Jeon YT, et al (2009). Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells. Ann NY Acad Sci, 1171, 495-500. https://doi.org/10.1111/j.1749-6632.2009.04899.x
  75. King FW, Fong S, Griffin C, et al (2009). Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress. PloS one, 4, 7283. https://doi.org/10.1371/journal.pone.0007283
  76. Kirken RA, Wang YL (2003). Molecular actions of sirolimus: sirolimus and mTor. Transplant Proc, 35, 227-30. https://doi.org/10.1016/S0041-1345(02)03856-3
  77. Kong D, Banerjee S, Huang W, et al (2008). Mammalian target of rapamycin repression by 3,3'-Diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor- D-overexpressing PC3 cells. Cancer Res, 68, 1927-34. https://doi.org/10.1158/0008-5472.CAN-07-3241
  78. Lao CD, Ruffin MTt, Normolle D, et al (2006). Dose escalation of a curcuminoid formulation. BMC Complement Altern Med, 6, 10. https://doi.org/10.1186/1472-6882-6-10
  79. Laplante M, Sabatini DM (2012). mTOR signalling in growth control and disease. Cell, 149, 274-93. https://doi.org/10.1016/j.cell.2012.03.017
  80. Laplante M, Sabatini DM (2013). Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci, 126, 1713-9. https://doi.org/10.1242/jcs.125773
  81. Law BK (2005). Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol, 56, 47-60. https://doi.org/10.1016/j.critrevonc.2004.09.009
  82. Le HT, Schaldach CM, Firestone GL, et al (2003). Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem, 278, 21136-45. https://doi.org/10.1074/jbc.M300588200
  83. Li JC, Zhu HY, Chen TX, et al (2013). Roles of mTOR and p-mTOR in gastrointestinal stromal tumors. Asian Pac J Cancer Prev, 14, 5925-8. https://doi.org/10.7314/APJCP.2013.14.10.5925
  84. Li M, Zhang Z, Hill DL, et al (2007). Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res, 67, 1988-96. https://doi.org/10.1158/0008-5472.CAN-06-3066
  85. Li Y, Sarkar FH (2002). Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signalling pathway. Clin Cancer Res, 8, 2369-77.
  86. Li Y, Wang Z, Kong D, et al (2007). Regulation of FOXO3a/betacatenin/ GSK-3beta signalling by 3,3'-Diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in prostate cancer cells. J Biol Chem, 282, 21542-50. https://doi.org/10.1074/jbc.M701978200
  87. Lin JN, Lin VC, Rau KM, et al (2010). Resveratrol modulates tumor cell proliferation and protein translation via SIRT1- dependent AMPK activation. J Agric Food Chem, 58, 1584-92. https://doi.org/10.1021/jf9035782
  88. Liu MJ, Wang Z, Ju Y, et al (2005). Diosgenin induces cell cycle arrest and apoptosis in human leukemia K562 cells with the disruption of Ca2+ homeostasis. Cancer Chemother Pharmacol, 55, 79-90. https://doi.org/10.1007/s00280-004-0849-3
  89. Liu P, Cheng H, Roberts TM, et al (2009a). Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov, 8, 627-44. https://doi.org/10.1038/nrd2926
  90. Liu Q, Thoreen C, Wang J, Sabatini D, Gray NS (2009b). mTOR mediated anti-cancer drug discovery. Drug Discov Today Ther Strateg, 6, 47-55. https://doi.org/10.1016/j.ddstr.2009.12.001
  91. Loewith R, Jacinto E, Wullschleger S, et al (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell, 10, 457-68. https://doi.org/10.1016/S1097-2765(02)00636-6
  92. LoPiccolo J, Blumenthal GM, Bernstein WB, et al (2008). Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat, 11, 32-50. https://doi.org/10.1016/j.drup.2007.11.003
  93. Malik A, Afaq F, Sarfaraz S, et al (2005). Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci USA, 102, 14813-8. https://doi.org/10.1073/pnas.0505870102
  94. Manning BD, Cantley LC (2007). AKT/PKB signalling: navigating downstream. Cell, 129, 1261-74. https://doi.org/10.1016/j.cell.2007.06.009
  95. Marques FZ, Markus MA, Morris BJ (2009). Resveratrol: cellular actions of a potent natural chemical that confers a diversity of health benefits. Int J Biochem Cell Biol, 41, 2125-8. https://doi.org/10.1016/j.biocel.2009.06.003
  96. Messing E, Gee JR, Saltzstein DR, et al (2012). A phase 2 cancer chemoprevention biomarker trial of isoflavone G-2535 (genistein) in presurgical bladder cancer patients. Cancer Prev Res, 5, 621-30. https://doi.org/10.1158/1940-6207.CAPR-11-0455
  97. Mita MM, Mita A, Rowinsky EK (2003). The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther, 2, 169-77.
  98. Moalic S, Liagre B, Corbiere C, et al (2001). A plant steroid, diosgenin, induces apoptosis, cell cycle arrest and COX activity in osteosarcoma cells. FEBS Lett, 506, 225-30. https://doi.org/10.1016/S0014-5793(01)02924-6
  99. Moschetta M, Reale A, Marasco C, et al (2014). Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations. Br J Pharmacol, [Epub ahead of print]
  100. Nagle DG, Ferreira D, Zhou YD (2006). Epigallocatechin-3- gallate (EGCG): chemical and biomedical perspectives. Phytochemistry, 67, 1849-55. https://doi.org/10.1016/j.phytochem.2006.06.020
  101. Nakamura Y, Yogosawa S, Izutani Y, et al (2009). A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol Cancer, 8, 100. https://doi.org/10.1186/1476-4598-8-100
  102. Nave BT, Ouwens M, Withers DJ, et al (1999). Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J, 344, 427-31. https://doi.org/10.1042/0264-6021:3440427
  103. Nicholson KM, Anderson NG (2002). The protein kinase B/ Akt signalling pathway in human malignancy. Cell Signal 14, 381-95. https://doi.org/10.1016/S0898-6568(01)00271-6
  104. Noh WC, Mondesire WH, Peng J, et al (2004). Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res, 10, 1013-23. https://doi.org/10.1158/1078-0432.CCR-03-0043
  105. O'Reilly KE, Rojo F, She QB, et al (2006). mTOR inhibition induces upstream receptor tyrosine kinase signalling and activates Akt. Cancer Res, 66, 1500-8. https://doi.org/10.1158/0008-5472.CAN-05-2925
  106. Pal I, Mandal M (2012). PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes. Acta Pharmacol Sin, 33, 1441-58. https://doi.org/10.1038/aps.2012.72
  107. Paller CJ, Ye X, Wozniak PJ, et al (2013). A randomized Phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis, 16, 50-5. https://doi.org/10.1038/pcan.2012.20
  108. Pandurangan AK (2013). Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways. Asian Pac J Cancer Prev, 14, 2201-5. https://doi.org/10.7314/APJCP.2013.14.4.2201
  109. Pantuck AJ, Leppert JT, Zomorodian N, et al (2006). Phase II study of pomegranate juice for men with rising prostatespecific antigen following surgery or radiation for prostate cancer. Clin Cancer Res, 12, 4018-26. https://doi.org/10.1158/1078-0432.CCR-05-2290
  110. Pervaiz S (2003). Resveratrol: from grapevines to mammalian biology. FASEB J, 17, 1975-85. https://doi.org/10.1096/fj.03-0168rev
  111. Peterson TR, Laplante M, Thoreen CC, et al (2009). DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 137, 873-86. https://doi.org/10.1016/j.cell.2009.03.046
  112. Philips BJ, Coyle CH, Morrisroe SN, et al (2009). Induction of apoptosis in human bladder cancer cells by green tea catechins. Biomed Res, 30, 207-15. https://doi.org/10.2220/biomedres.30.207
  113. Plas DR, Thompson CB (2005). Akt-dependent transformation: there is more to growth than just surviving. Oncogene, 24, 7435-42. https://doi.org/10.1038/sj.onc.1209097
  114. Popat R, Plesner T, Davies F, et al (2013). A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br J Haematol 160, 714-7. https://doi.org/10.1111/bjh.12154
  115. Porta C, Paglino C, Mosca A (2014). Targeting PI3K/Akt/mTOR signalling in cancer. Fron Oncol, 4, 64.
  116. Powers T, Walter P (1999). Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signalling pathway in Saccharomyces cerevisiae. Mol Biol Cell, 10, 987-1000. https://doi.org/10.1091/mbc.10.4.987
  117. Proud CG (2002). Regulation of mammalian translation factors by nutrients. Eur J Biochem, 269, 5338-49. https://doi.org/10.1046/j.1432-1033.2002.03292.x
  118. Pyrko P, Schonthal AH, Hofman FM, et al (2007). The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res, 67, 9809-16. https://doi.org/10.1158/0008-5472.CAN-07-0625
  119. Qiao Y, Cao J, Xie L, et al (2009). Cell growth inhibition and gene expression regulation by (-)-epigallocatechin-3-gallate in human cervical cancer cells. Arch Pharm Res, 32, 1309-15. https://doi.org/10.1007/s12272-009-1917-3
  120. Ravindranath MH, Muthugounder S, Presser N, et al (2004). Anticancer therapeutic potential of soy isoflavone, genistein. Adv Exp Med Biol, 546, 121-65. https://doi.org/10.1007/978-1-4757-4820-8_11
  121. Rodon J, Dienstmann R, Serra V, et al (2013). Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol, 10, 143-53. https://doi.org/10.1038/nrclinonc.2013.10
  122. Ryan JL, Heckler CE, Ling M, et al (2013). Curcumin for radiation dermatitis: a randomized, double-blind, placebocontrolled clinical trial of thirty breast cancer patients. Radiat Res, 180, 34-43. https://doi.org/10.1667/RR3255.1
  123. Sabatini DM, Erdjument-Bromage H, Lui M, et al (1994). RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell, 78, 35-43. https://doi.org/10.1016/0092-8674(94)90570-3
  124. Sabers CJ, Martin MM, Brunn GJ, et al (1995). Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem, 270, 815-22. https://doi.org/10.1074/jbc.270.2.815
  125. Sakamoto T, Horiguchi H, Oguma E, et al (2010). Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J Nutr Biochem, 21, 856-64. https://doi.org/10.1016/j.jnutbio.2009.06.010
  126. Sancak Y, Thoreen CC, Peterson TR, et al (2007). PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell, 25, 903-15.
  127. Sansal I, Sellers WR (2004). The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol, 22, 2954-63. https://doi.org/10.1200/JCO.2004.02.141
  128. Sarbassov DD, Ali SM, Kim DH, et al (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol, 14, 1296-302. https://doi.org/10.1016/j.cub.2004.06.054
  129. Sarbassov DD, Ali SM, Sengupta S, et al (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/ PKB. Mol Cell, 22, 159-68. https://doi.org/10.1016/j.molcel.2006.03.029
  130. Sehgal SN, Baker H, Vezina C (1975). Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo), 28, 727-32. https://doi.org/10.7164/antibiotics.28.727
  131. Seo BR, Min KJ, Cho IJ, et al (2014). Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235- induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability. PloS one, 9, 95588. https://doi.org/10.1371/journal.pone.0095588
  132. Sharma RA, McLelland HR, Hill KA, et al (2001). Pharmacodynamic and pharmacokinetic study of oral curcuma extract in patients with colorectal cancer. Clin Cancer Res, 7, 1894-900.
  133. Sharp Z, Richardson A (2011). Aging and cancer: can mTOR inhibitors kill two birds with one drug? Target Oncol, 6, 41-51. https://doi.org/10.1007/s11523-011-0168-7
  134. Shimobayashi M, Hall MN (2014). Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol, 15, 155-62. https://doi.org/10.1038/nrm3757
  135. Shishodia S, Chaturvedi MM, Aggarwal BB (2007). Role of curcumin in cancer therapy. Curr Probl Cance, 31, 243-305. https://doi.org/10.1016/j.currproblcancer.2007.04.001
  136. Shor B, Gibbons JJ, Abraham RT, et al (2009). Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 8, 3831-7. https://doi.org/10.4161/cc.8.23.10070
  137. Soliman GA, Acosta-Jaquez HA, Dunlop EA, et al (2010). mTOR Ser-2481 autophosphorylation monitors mTORCspecific catalytic activity and clarifies rapamycin mechanism of action. J Biol Chem, 285, 7866-79. https://doi.org/10.1074/jbc.M109.096222
  138. Srinivasan S, Koduru S, Kumar R, et al (2009). Diosgenin targets Akt-mediated prosurvival signalling in human breast cancer cells. Int J Cancer, 125, 961-7. https://doi.org/10.1002/ijc.24419
  139. Sun J, Chu Y-F, Wu X, et al (2002). Antioxidant and antiproliferative activities of common fruits. J Agric Food Chem, 50, 7449-54. https://doi.org/10.1021/jf0207530
  140. Sun SY, Rosenberg LM, Wang X, et al (2005). Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res, 65, 7052-8. https://doi.org/10.1158/0008-5472.CAN-05-0917
  141. Sy LK, Yan SC, Lok CN, et al (2008). Timosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells. Cancer Res, 68, 10229-37. https://doi.org/10.1158/0008-5472.CAN-08-1983
  142. Tabernero J, Rojo F, Calvo E, et al (2008). Dose- and scheduledependent inhibition of the mammalian target of rapamycin pathway with everolimus: a Phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26, 1603-10. https://doi.org/10.1200/JCO.2007.14.5482
  143. Takahashi Y, Kohashi K, Yamada Y, et al (2014). Activation of the Akt/mammalian target of rapamycin pathway in myxofibrosarcomas. Human pathol, 45, 984-93. https://doi.org/10.1016/j.humpath.2013.12.012
  144. Tang KD, Ling MT (2014). Targeting Drug-Resistant Prostate Cancer with Dual PI3K/MTOR Inhibition. Curr Med Chem, [Epub ahead of print].
  145. Tokunaga E, Oki E, Egashira A, et al (2008). Deregulation of the Akt pathway in human cancer. Curr Cancer Drug Targets, 8, 27-36. https://doi.org/10.2174/156800908783497140
  146. Tsang CK, Qi H, Liu LF, et al (2007). Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today, 12, 112-24. https://doi.org/10.1016/j.drudis.2006.12.008
  147. Vakana E, Sassano A, Platanias LC (2010). Induction of autophagy by dual mTORC1-mTORC2 inhibition in BCRABL- expressing leukemic cells. Autophagy, 6, 966-7. https://doi.org/10.4161/auto.6.7.13067
  148. Vezina C, Kudelski A, Sehgal SN (1975). Rapamycin (AY- 22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot, 28, 721-6. https://doi.org/10.7164/antibiotics.28.721
  149. Vivanco I, Sawyers CL (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer, 2, 489-501. https://doi.org/10.1038/nrc839
  150. Vogt PK, Hart JR, Gymnopoulos M, et al (2010). Phosphatidylinositol 3-kinase: the oncoprotein. Curr Top Microbiol Immunol, 347, 79-104.
  151. Wan X, Harkavy B, Shen N, et al (2007). Rapamycin induces feedback activation of Akt signalling through an IGF-1Rdependent mechanism. Oncogene, 26, 1932-40. https://doi.org/10.1038/sj.onc.1209990
  152. Wang XW, Zhang YJ (2014). Targeting mTOR network in colorectal cancer therapy. World J Gastroenterol, 20, 4178-88. https://doi.org/10.3748/wjg.v20.i15.4178
  153. Wu Y, Kim J, Elshimali Y, et al (2014). Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice. BMC Cancer, 14, 266. https://doi.org/10.1186/1471-2407-14-266
  154. Yap TA, Garrett MD, Walton MI, et al (2008). Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol, 8, 393-412. https://doi.org/10.1016/j.coph.2008.08.004
  155. Yu K, Toral-Barza L, Discafani C, et al (2001). mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer, 8, 249-58. https://doi.org/10.1677/erc.0.0080249
  156. Zhang J, Meng Z, Zhang M, et al (1999). Effect of six steroidal saponins isolated from anemarrhenae rhizoma on platelet aggregation and hemolysis in human blood. Clin Chim Acta, 289, 79-88. https://doi.org/10.1016/S0009-8981(99)00160-6
  157. Zhang Q, Kelly AP, Wang L, et al (2006). Green tea extract and (-)-epigallocatechin-3-gallate inhibit mast cell-stimulated type I collagen expression in keloid fibroblasts via blocking PI-3K/AkT signalling pathways. J Invest Dermatol, 126, 2607-13. https://doi.org/10.1038/sj.jid.5700472
  158. Zhao JJ, Cheng H, Jia S, et al (2006). The $p110{\alpha}$ isoform of PI3K is essential for proper growth factor signalling and oncogenic transformation. Proc Natl Acad Sci USA, 103, 16296-300. https://doi.org/10.1073/pnas.0607899103

Cited by

  1. Molecular Mechanisms of Casticin Action: an Update on its Antitumor Functions vol.15, pp.21, 2014, https://doi.org/10.7314/APJCP.2014.15.21.9049
  2. Phytometabolite Dehydroleucodine Induces Cell Cycle Arrest, Apoptosis, and DNA Damage in Human Astrocytoma Cells through p73/p53 Regulation vol.10, pp.8, 2015, https://doi.org/10.1371/journal.pone.0136527
  3. Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model vol.15, pp.23, 2015, https://doi.org/10.7314/APJCP.2014.15.23.10463
  4. MiR-99a Inhibits Cell Proliferation and Tumorigenesis through Targeting mTOR in Human Anaplastic Thyroid Cancer vol.16, pp.12, 2015, https://doi.org/10.7314/APJCP.2015.16.12.4937
  5. Metformin Addition to Chemotherapy in Stage IV Non-Small Cell Lung Cancer: an Open Label Randomized Controlled Study vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6621
  6. Evaluation of the antiaggregant activity of ascorbyl phenolic esters with antioxidant properties vol.71, pp.3, 2015, https://doi.org/10.1007/s13105-015-0421-0
  7. Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells vol.17, pp.3, 2016, https://doi.org/10.7314/APJCP.2016.17.3.1103
  8. Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53 vol.17, pp.3, 2016, https://doi.org/10.7314/APJCP.2016.17.3.993
  9. N-Hydroxyphthalimide exhibits antitumor activity by suppressing mTOR signaling pathway in BT-20 and LoVo cells vol.35, pp.1, 2016, https://doi.org/10.1186/s13046-016-0315-1
  10. Plant phenols and autophagy vol.81, pp.4, 2016, https://doi.org/10.1134/S0006297916040015
  11. The Impact of Soy Isoflavones on MCF-7 and MDA-MB-231 Breast Cancer Cells Using a Global Metabolomic Approach vol.17, pp.9, 2016, https://doi.org/10.3390/ijms17091443
  12. Mammalian target of rapamycin inhibitor RAD001 sensitizes endometrial cancer cells to paclitaxel-induced apoptosis via the induction of autophagy vol.12, pp.6, 2016, https://doi.org/10.3892/ol.2016.5338
  13. Inhibition of mTOR/S6K1/4E-BP1 Signaling by Nutraceutical SIRT1 Modulators vol.70, pp.3, 2018, https://doi.org/10.1080/01635581.2018.1446093