Activity of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in hepatocellular carcinoma

Liver International

Volumn 33, Issue 5, 2013, Pages 780-793

  Kirstein, Martha M ^a   Boukouris, Aristeidis E ^a   Pothiraju, Deepika ^a   Buitrago Molina, Laura E ^a   Marhenke, Silke ^a   Schütt, Jutta ^a   Orlik, Johanna ^a   Kühnel, Florian ^a   Hegermann, Jan ^a   Manns, Michael P ^a   Vogel, Arndt ^a  

^a HANNOVER MEDICAL SCHOOL   (Germany)

Author keywords

Hepatocellular carcinoma; MTOR; PI3 kinase

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; BUPARLISIB; CISPLATIN; DOXORUBICIN; EVEROLIMUS; FLUOROURACIL; IRINOTECAN;

ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; AUTOPHAGY; CANCER COMBINATION CHEMOTHERAPY; CELL CYCLE PROGRESSION; CELL VIABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; GLYCOLYSIS; HEPATOMA CELL; HISTOPATHOLOGY; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL CARCINOMA; MITOCHONDRIAL RESPIRATION; NICK END LABELING; OXIDATIVE PHOSPHORYLATION; SIGNAL TRANSDUCTION; TUMOR CELL; TUMOR XENOGRAFT;

AMINOPYRIDINES; ANALYSIS OF VARIANCE; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; AUTOPHAGY; CAMPTOTHECIN; CARCINOMA, HEPATOCELLULAR; CELL CYCLE; CELL LINE; CELL RESPIRATION; CISPLATIN; DOXORUBICIN; HUMANS; IMIDAZOLES; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; IN SITU NICK-END LABELING; LIVER NEOPLASMS; MORPHOLINES; PHOSPHATIDYLINOSITOL 3-KINASES; QUINOLINES; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84876092424     PISSN: 14783223     EISSN: 14783231     Source Type: Journal    
DOI: 10.1111/liv.12126     Document Type: Article

References (40)

1. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 134: 1752-63.
2. Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008; 135: 1972-83, 83 e1-11.
3. Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004; 10: 8421-5.
4. Buitrago-Molina LE, Pothiraju D, Lamle J, et al. Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage. Hepatology 2009; 50: 500-9.
5. Zhu AX, Abrams TA, Miksad R, et al. Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer 2011; 117: 5094-102.
6. Rizell M, Andersson M, Cahlin C, et al. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 2008; 13: 66-70.
7. Schoniger-Hekele M, Muller C. Pilot study: rapamycin in advanced hepatocellular carcinoma. Aliment Pharmacol Ther 2010; 32: 763-8.
8. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118: 3065-74.
9. Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022-30.
10. Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008; 14: 1351-6.
11. Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851-63.
12. Cao P, Maira SM, Garcia-Echeverria C, Hedley DW. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer 2009; 100: 1267-76.
13. Cho DC, Cohen MB, Panka DJ, et al. The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin Cancer Res 2010; 16: 3628-38.
14. Thomas HE, Mercer CA, Carnevalli LS, et al. mTOR Inhibitors Synergize Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma. Sci Transl Med 2012; 4: 139ra84.
15. Voliva CF, Pecchi S, Burger M, et al. Biological characterization of NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials. Cancer Res 2010; 70(8 suppl 1): 4498.
16. Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022-30.
17. Bendell JC, Rodon J, Burris HA, et al. dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012; 30: 282-90.
18. Reynolds ES. The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. J Cell Biol 1963; 17: 208-13.
19. Vogel A, van Den Berg IE, Al-Dhalimy M, et al. Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death. Hepatology 2004; 39: 433-43.
20. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22.
21. Diaz-Troya S, Perez-Perez ME, Florencio FJ, Crespo JL. The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 2008; 4: 851-65.
22. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132-41.
23. Wang RC, Wei Y, An Z, et al. Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation. Science 2012; 338: 956-9.
24. Cunningham JT, Rodgers JT, Arlow DH, et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1a transcriptional complex. Nature 2007; 450: 736-40.
25. Schieke SM, Phillips D, McCoy JP Jr, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 2006; 281: 27643-52.
26. Ramanathan A, Schreiber SL. Direct control of mitochondrial function by mTOR. PNAS 2009; 106: 22229-32.
27. Goggin MM, Nelsen CJ, Kimball SR, et al. Rapamycin-sensitive induction of eukaryotic initiation factor 4F in regenerating mouse liver. Hepatology 2004; 40: 537-44.
28. Nelsen CJ, Rickheim DG, Tucker MM, Hansen LK, Albrecht JH. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem 2003; 278: 3656-63.
29. Cho DC, Cohen MB, Panka DJ, et al. The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin Cancer Res 2010; 16: 3628-38.
30. Dong J, Peng J, Zhang H, et al. Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res 2005; 65: 1961-72.
31. Wanner K, Hipp S, Oelsner M, et al. Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol 2006; 134: 475-84.
32. Maiuri MC, Tasdemir E, Criollo A, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 2009; 16: 87-93.
33. Mabuchi S, Altomare DA, Connolly DC, et al. RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res 2007; 67: 2408-13.
34. Schlosshauer PW, Li W, Lin KT, Chan JL, Wang LH. Rapamycin by itself and additively in combination with carboplatin inhibits the growth of ovarian cancer cells. Gynecol Oncol 2009; 114: 516-22.
35. Manara MC, Nicoletti G, Zambelli D, et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res 2010; 16: 530-40.
36. Beuvink I, Boulay A, Fumagalli S, et al. The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 Translation. Cell 2005; 120: 747-59.
37. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500-8.
38. Newell P, Toffanin S, Villanueva A, et al. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 2009; 51: 725-33.
39. Wang Z, Zhou J, Fan J, et al. Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 2008; 14: 5124-30.
40. Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 2008; 15: 521-9.