mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

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• 作者：Huiyuan Zhang (1) (2)
  Jun Dou (3) (4)
  Yang Yu (2)
  Yanling Zhao (2)
  Yihui Fan (2)
  Jin Cheng (2)
  Xin Xu (2)
  Wei Liu (2)
  Shan Guan (2)
  Zhenghu Chen (2)
  Yan shi (5)
  Roma Patel (5)
  Sanjeev A. Vasudevan (5)
  Peter E. Zage (2)
  Hong Zhang (3)
  Jed G. Nuchtern (5)
  Eugene S. Kim (5)
  Songbin Fu (1)
  Jianhua Yang (2)
  
• 关键词：Neuroblastoma ; mTOR inhibitor ; INK128 ; Chemotherapy ; Drug resistance
• 刊名：Apoptosis
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：20
• 期：1
• 页码：50-62
• 全文大小：1,334 KB
• 参考文献：1. Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203鈥?16 CrossRef
  2. Schwab M, Westermann F, Hero B, Berthold F (2003) Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4:472鈥?80 CrossRef
  3. Jacinto E, Hall MN (2003) Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 4:117鈥?26 CrossRef
  4. Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR et al (2010) Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17:249鈥?61 CrossRef
  5. Li J, Xue L, Hao H, Han Y, Yang J, Luo J (2012) Rapamycin provides a therapeutic option through inhibition of mTOR signaling in chronic myelogenous leukemia. Oncol Rep 27:461鈥?66
  6. Hirase C, Maeda Y, Takai S, Kanamaru A (2009) Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: possible clinical application of mTOR inhibitor. Leuk Res 33:450鈥?59 CrossRef
  7. Glienke W, Maute L, Wicht J, Bergmann L (2012) The dual PI3聽K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines. Tumour Biol 33:757鈥?65 CrossRef
  8. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 1804:433鈥?39 CrossRef
  9. Shor B, Gibbons JJ, Abraham RT, Yu K (2009) Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 8:3831鈥?837 CrossRef
  10. Sparks CA, Guertin DA (2010) Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29:3733鈥?744 CrossRef
  11. Foster DA, Toschi A (2009) Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle 8:1026鈥?029 CrossRef
  12. Johnsen JI, Segerstrom L, Orrego A, Elfman L, Henriksson M, K氓gedal B et al (2008) Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene 27:2910鈥?922 CrossRef
  13. Schenone S, Brullo C, Musumeci F, Radi M, Botta M (2011) ATP-competitive inhibitors of mTOR: an update. Curr Med Chem 18:2995鈥?014 CrossRef
  14. Lou H, Dean M (2007) Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene 26:1357鈥?360 CrossRef
  15. Glunde K, Jiang L, Moestue SA, Gribbestad IS (2011) MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer. NMR Biomed 24:673鈥?90
  16. Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: cancer鈥檚 double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25:4777鈥?786 CrossRef
  17. Dazert E, Hall MN (2011) mTOR signaling in disease. Curr Opin Cell Biol 23:744鈥?55 CrossRef
  18. Fan YH, Cheng J, Vasudevan SA, Dou J, Zhang H, Ratal RH et al (2013) USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis. Cell Death Dis 4:e867 CrossRef
  19. Cheng J, Fan YH, Xu X, Zhang H, Dou J, Tang Y et al (2014) A small-molecule inhibitor of UBE2聽N induces neuroblastoma cell death via activation of p53 and JNK pathways. Cell Death Dis 5:e1079 CrossRef
  20. Maki CG (2010) Decision-making by p53 and mTOR. Aging 2:324鈥?26
  21. Zhou H, Huang S (2010) mTOR signaling in cancer cell motility and tumor metastasis. Crit Rev Eukaryot Gene Expr 20:1鈥?6 CrossRef
  22. Wan X, Helman LJ (2007) The biology behind mTOR inhibition in sarcoma. Oncologist 12:1007鈥?018 CrossRef
  23. Berry T, Luther W, Bhatnagar N, Jamin Y, Poon E, Sanda T et al (2012) The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell 22:117鈥?30 CrossRef
  24. Li J, Kim SG, Blenis J (2014) Rapamycin: one drug, many effects. Cell Metab 19:373鈥?79 CrossRef
  25. Richard DJ, Verheijen JC, Zask A (2010) Recent advances in the development of selective, ATP-competitive inhibitors of mTOR. Curr Opin Drug Discov Devel 13:428鈥?40
  26. Garcia-Echeverria C (2010) Allosteric and ATP-competitive kinase inhibitors of mTOR for cancer treatment. Bioorg Med Chem Lett 20:4308鈥?312 CrossRef
  27. Albert S, Serova M, Dreyer C, Sablin MP, Faivre S, Raymond E (2010) New inhibitors of themammalian target of rapamycin signaling pathway for cancer. Expert Opin Investig Drugs 19:919鈥?30 CrossRef
  28. Janes MR, Vu C, Mallya S et al (2013) Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. Leukemia 27:586鈥?94 CrossRef
  29. Wacheck V (2010) mTOR pathway inhibitors in cancer therapy: moving past rapamycin. Pharmacogenomics 11:1189鈥?191 CrossRef
  30. Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269鈥?70
  31. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425鈥?34 CrossRef
  32. Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P (2005) Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia 19:2153鈥?158 CrossRef
  33. Das A, Banik NL, Ray SK (2009) Retinoids induce differentiation and downregulate telomerase activity and N-Myc to increase sensitivity to flavonoids for apoptosis in human malignant neuroblastoma SH-SY5Y cells. Int J Oncol 34:757鈥?65
  34. Prochazka P, Hrabeta J, Vicha A, Cipro S, Stejskalova E, Musil Z et al (2013) Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers. Oncol Rep 29:2415鈥?421
  35. Calero R, Morchon E, Johnsen JI, Serrano R (2014) Sunitinib suppress neuroblastoma growth through degradation of MYCN and inhibition of angiogenesis. PLoS ONE 9:e95628 CrossRef
  36. Kushner BH, Modak S, Kramer K, LaQuaglia MP, Yataghene K, Basu EM et al (2014) Striking dichotomy in outcome of MYCN-amplified neuroblastoma in the contemporary era. Cancer 120:2050鈥?059 CrossRef
  37. Modak S, Cheung NK (2010) Neuroblastoma: therapeutic strategies for a clinical enigma. Cancer Treat Rev 36:307鈥?17 CrossRef
  38. Gustafson WC, Weiss WA (2010) Myc proteins as therapeutic targets. Oncogene 29:1249鈥?259 CrossRef
  39. Fulda S (2009) The PI3聽K/Akt/mTOR pathway as therapeutic target in neuroblastoma. Curr Cancer Drug Targets 9:729鈥?37 CrossRef
  40. Burris HA 3rd (2013) Overcoming acquired resistance to anticancer therapy: focus on the PI3聽K/AKT/mTOR pathway. Cancer Chemother Pharmacol 71:829鈥?42 CrossRef
  41. Liu H, Scholz C, Zang C, Schefe JH, Habbel P, Regierer AC et al (2012) Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res 32:1627鈥?637
  42. Wang ZG, Fukazawa T, Nishikawa T, Watanabe N, Sakurama K, Motoki T et al (2010) RAD001 offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer. Oncol Rep 23:1167鈥?172
  43. Mishra R, Miyamoto M, Yoshioka T, Ishikawa K, Matsumura Y, Shoji Y et al (2009) Adenovirus- mediated eukaryotic initiation factor 4E binding protein-1 in combination with rapamycin inhibits tumor growth of pancreatic ductal adenocarcinoma in vivo. Int J Oncol 34:1231鈥?240
  44. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM et al (2010) A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol 85:320鈥?24
  45. Nagai T, Ohmine K, Fujiwara S, Uesawa M, Sakurai C, Ozawa K (2010) Combination of tipifarnib and rapamycin synergistically inhibits the growth of leukemia cells and overcomes resistance to tipifarnib via alteration of cellular signaling pathways. Leuk Res 34:1057鈥?063 CrossRef
  46. Piguet AC, Semela D, Keogh A, Wilkens L, Stroka D, Stoupis C et al (2008) Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma. J Hepatol 49:78鈥?7 CrossRef
  47. Kim ES, Serur A, Huang J, Manley CA, McCrudden KW, Frischer JS et al (2002) Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci USA 99:11399鈥?1404 CrossRef
  48. Patterson DM, Shohet JM, Kim ES (2011) Preclinical models of pediatric solid tumors (neuroblastoma) and their use in drug discovery. Curr Protoc Pharmacol. doi:10.1002/0471141755.ph1417s52
  
• 作者单位：Huiyuan Zhang (1) (2)
  Jun Dou (3) (4)
  Yang Yu (2)
  Yanling Zhao (2)
  Yihui Fan (2)
  Jin Cheng (2)
  Xin Xu (2)
  Wei Liu (2)
  Shan Guan (2)
  Zhenghu Chen (2)
  Yan shi (5)
  Roma Patel (5)
  Sanjeev A. Vasudevan (5)
  Peter E. Zage (2)
  Hong Zhang (3)
  Jed G. Nuchtern (5)
  Eugene S. Kim (5)
  Songbin Fu (1)
  Jianhua Yang (2)
  
  1. Labratory of Medical Genetics, Harbin Medical University, 157 Baojian Rd, Nangang Dist, Harbin, 150081, Heilongjiang, China
  2. Texas Children鈥檚 Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
  3. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
  4. Xinjiang Key Laboratory of Plant Resources and Natural Products Chemistry, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, Xinjiang, China
  5. Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Cancer Research
  Cell Biology
  Biochemistry
  Virology
  
• 出版者：Springer Netherlands
• ISSN：1573-675X

文摘

High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.