The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells

Oncotarget

Volumn 6, Issue 19, 2015, Pages 17147-17160

  Simioni, Carolina ^a   Cani, Alice ^a   Martelli, Alberto M ^b   Zauli, Giorgio ^c   Alameen, Ayman A M ^a,d   Ultimo, Simona ^a   Tabellini, Giovanna ^e   McCubrey, James A ^f   Capitani, Silvano ^a   Neri, Luca M ^a  

^a UNIVERSITY OF FERRARA   (Italy)

^b UNIVERSITY OF BOLOGNA   (Italy)

^c INSTITUTE FOR MATERNAL AND CHILD HEALTH IRCCS BURLO GAROFOLO   (Italy)

^d UNIVERSITY OF KHARTOUM   (Sudan)

^e UNIVERSITY OF BRESCIA   (Italy)

^f EAST CAROLINA UNIVERSITY   (United States)

Author keywords

Hepatocellular carcinoma; Hypoxia; NVP BGT226; PI3K Akt signaling; Targeted therapies

Indexed keywords

8 (6 METHOXY 3 PYRIDINYL) 3 METHYL 1 [4 (1 PIPERAZINYL) 3 (TRIFLUOROMETHYL)PHENYL] 1H IMIDAZO[4,5 C]QUINOLIN 2(3H) ONE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; S6 KINASE; VASCULOTROPIN; 8-(6-METHOXYPYRIDIN-3-YL)-3-METHYL-1-(4-PIPERAZIN-1-YL-3-TRIFLUOROMETHYLPHENYL)-1,3-DIHYDROIMIDAZO(4,5-C)QUINOLIN-2-ONE; ANTINEOPLASTIC AGENT; IMIDAZOLE DERIVATIVE; MTOR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; QUINOLINE DERIVATIVE; TARGET OF RAPAMYCIN KINASE;

ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; AUTOPHAGY; CARCINOMA CELL LINE; CELL HYPOXIA; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG POTENCY; G1 PHASE CELL CYCLE CHECKPOINT; LIVER CELL CARCINOMA; LIVER CELL CARCINOMA CELL LINE; MTT ASSAY; TRANSCRIPTION REGULATION; WESTERN BLOTTING; ANTAGONISTS AND INHIBITORS; CELL CYCLE CHECKPOINT; DRUG EFFECTS; HUMAN; LIVER TUMOR; PATHOLOGY; SIGNAL TRANSDUCTION; TUMOR CELL LINE;

ANTINEOPLASTIC AGENTS; APOPTOSIS; AUTOPHAGY; BLOTTING, WESTERN; CARCINOMA, HEPATOCELLULAR; CELL CYCLE CHECKPOINTS; CELL HYPOXIA; CELL LINE, TUMOR; HUMANS; IMIDAZOLES; LIVER NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; QUINOLINES; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84938254831     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.3940     Document Type: Article

References (72)

1. Shirabe K, Toshima T, Taketomi A, Taguchi K, Yoshizumi T, Uchiyama H, Harimoto N, Kajiyama K, Egashira A, Maehara Y. Hepatic aflatoxin B1-DNA adducts and TP53 mutations in patients with hepatocellular carcinoma despite low exposure to aflatoxin B1 in southern Japan. Liver Int. 2011; 31:1366-1372.
2. Shirabe K, Itoh S, Yoshizumi T, Soejima Y, Taketomi A, Aishima S, Maehara Y. The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference to the serum levels of des-gamma-carboxy prothrombin. J Surg Oncol. 2007; 95:235-240.
3. Shirabe K, Kajiyama K, Harimoto N, Tsujita E, Wakiyama S, Maehara Y. Risk factors for massive bleeding during major hepatectomy. World J Surg. 2010; 34:1555-1562.
4. Bruix J, Llovet JM. Prognostic assessment and evaluation of the benefits of treatment. J Clin Gastroenterol. 2002; 35:S138-142.
5. Zhuang PY, Wang JD, Tang ZH, Zhou XP, Yang Y, Quan ZW, Liu YB, Shen J. Peritumoral Neuropilin-1 and VEGF receptor-2 expression increases time to recurrence in hepatocellular carcinoma patients undergoing curative hepatectomy. Oncotarget. 2014; 5:11121-11132.
6. Davis GL, Dempster J, Meler JD, Orr DW, Walberg MW, Brown B, Berger BD, O'Connor JK, Goldstein RM. Hepatocellular carcinoma: management of an increasingly common problem. Proc (Bayl Univ Med Cent). 2008; 21:266-280.
7. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009; 10:25-34.
8. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359:378-390.
9. Kim R, Byrne MT, Tan A, Aucejo F. What is the indication for sorafenib in hepatocellular carcinoma? A clinical challenge. Oncology (Williston Park). 2011; 25:283-291.
10. Janku F, Kaseb AO, Tsimberidou AM, Wolff RA, Kurzrock R. Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget. 2014; 5:3012-3022.
11. Katanasaka Y, Kodera Y, Yunokawa M, Kitamura Y, Tamura T, Koizumi F. Synergistic anti-tumor effects of a novel phosphatidyl inositol-3 kinase/mammalian target of rapamycin dual inhibitor BGT226 and gefitinib in non-small cell lung cancer cell lines. Cancer Lett. 2014; 347:196-203.
12. Janes MR, Fruman DA. Targeting TOR dependence in cancer. Oncotarget. 2010; 1:69-76.
13. Eyre TA, Collins GP, Goldstone AH, Cwynarski K. Time now to TORC the TORC? New developments in mTOR pathway inhibition in lymphoid malignancies. Br J Haematol. 2014; 166:336-351.
14. Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes & development. 2006; 20:3347-3365.
15. Jiang BH, Liu LZ. AKT signaling in regulating angiogenesis. Curr Drug Targets. 2008; 8:19-26.
16. Brown JM. Tumor hypoxia in cancer therapy. Methods Enzymol. 2007; 435:297-321.
17. Choi SB, Park JB, Song TJ, Choi SY. Molecular mechanism of HIF-1-independent VEGF expression in a hepatocellular carcinoma cell line. Int J Mol Med. 2011; 28:449-454.
18. Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, Mita M, Melendez Cuero M, Stutvoet S, Birle D, Anak O, Hackl W, Baselga J. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol. 2012; 23:2399-2408.
19. Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer BA, Liebermann M, Falkenburg JH, Ruthardt M, Ottmann OG. Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PloS one. 2013; 8:e80070.
20. Lee JH, Lee H, Yun SM, Jung KH, Jeong Y, Yan HH, Hong S, Hong SS. IPD-196, a novel phosphatidylinositol 3-kinase inhibitor with potent anticancer activity against hepatocellular carcinoma. Cancer Lett. 2013; 329:99-108.
21. Simioni C, Martelli AM, Cani A, Cetin-Atalay R, McCubrey JA, Capitani S, Neri LM. The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy. Oncotarget. 2013; 4:1496-1506.
22. Chang AY, Wang M. Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS-354825) on hepatocellular carcinoma cells. BMC cancer. 2013; 13:267.
23. Wang J, Zheng X, Zeng G, Zhou Y, Yuan H. Purified vitexin compound 1 inhibits growth and angiogenesis through activation of FOXO3a by inactivation of Akt in hepatocellular carcinoma. Int J Mol Med. 2014; 33:441-448.
24. Wilson JM, Kunnimalaiyaan S, Gamblin TC, Kunnimalaiyaan M. MK2206 inhibits hepatocellular carcinoma cellular proliferation via induction of apoptosis and cell cycle arrest. J Surg Res. 2014; 191:280-285.
25. Grabinski N, Ewald F, Hofmann BT, Staufer K, Schumacher U, Nashan B, Jucker M. Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells. Mol Cancer. 2012; 11:85.
26. Chang KY, Tsai SY, Wu CM, Yen CJ, Chuang BF, Chang JY. Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo. Clin Cancer Res. 2011; 17:7116-7126.
27. Baumann P, Schneider L, Mandl-Weber S, Oduncu F, Schmidmaier R. Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma. Anti-cancer Drugs. 2012; 23:131-138.
28. Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, Lin L, Ellis MJ. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. BCR. 2011; 13:R21.
29. Fokas E, Yoshimura M, Prevo R, Higgins G, Hackl W, Maira SM, Bernhard EJ, McKenna WG, Muschel RJ. NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. Radiat Oncol. 2012; 7:48.
30. Glienke W, Maute L, Wicht J, Bergmann L. The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines. Tumour Biol. 2012; 33:757-765.
31. Mu Q, Ma Q, Lu S, Zhang T, Yu M, Huang X, Chen J, Jin J. 10058-F4, a c-Myc inhibitor, markedly increases valproic acid-induced cell death in Jurkat and CCRF-CEM T-lymphoblastic leukemia cells. Oncol Lett. 2014; 8:1355-1359.
32. Wallington-Beddoe CT, Hewson J, Bradstock KF, Bendall LJ. FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells. Autophagy. 2011; 7:707-715.
33. Pankiv S, Clausen TH, Lamark T, Brech A, BruunJA, Outzen H, Overvatn A, Bjorkoy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007; 282:24131-24145.
34. Kung CP, Budina A, Balaburski G, Bergenstock MK, Murphy M. Autophagy in tumor suppression and cancer therapy. Crit Rev Eucaryot Gene Expr. 2011; 21:71-100.
35. Wang L, Gao C, Yao S, Xie B. Blocking autophagic flux enhances matrine-induced apoptosis in human hepatoma cells. Int J Mol Sci. 2013; 14:23212-23230.
36. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, Ahn HJ, Ait-Mohamed O, Ait-Si-Ali S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012; 8:445-544.
37. Harris AL. Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer. 2002; 2:38-47.
38. Weinmann M, Jendrossek V, Handrick R, Guner D, Goecke B, Belka C. Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner. Oncogene. 2004; 23:3757-3769.
39. Nagarajah NS, Vigneswaran N, Zacharias W. Hypoxia-mediated apoptosis in oral carcinoma cells occurs via two independent pathways. Mol Cancer. 2004; 3:38.
40. McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D'Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006; 46:249-279.
41. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003; 2:339-345.
42. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, Donia M, Fagone P, Malaponte G, et al. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging. 2011; 3:192-222.
43. Ruan ZP, Xu R, Lv Y, Tian T, Wang WJ, Guo H, Nan KJ. PTEN enhances the sensitivity of human hepatocellular carcinoma cells to sorafenib. Oncol Res. 2012; 20:113-121.
44. O'Brien C, Wallin JJ, Sampath D, GuhaThakurta D, Savage H, Punnoose EA, Guan J, Berry L, Prior WW, Amler LC, Belvin M, Friedman LS, Lackner MR. Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res. 2010; 16:3670-3683.
45. Liang X, Tang J, Liang Y, Jin R, Cai X. Suppression of autophagy by chloroquine sensitizes 5-fluorouracil-mediated cell death in gallbladder carcinoma cells. Cell & Bioscience. 2014; 4:10.
46. Xu ZX, Liang J, Haridas V, Gaikwad A, Connolly FP, Mills GB, Gutterman JU. A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase. Cell Death Differ. 2007; 14:1948-1957.
47. Yu HC, Lin CS, Tai WT, Liu CY, Shiau CW, Chen KF. Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation. J Biol Chem. 2013; 288:18249-18259.
48. Martins I, Galluzzi L, Kroemer G. Hormesis, cell death and aging. Aging. 2011; 3:821-828.
49. Evangelisti C, Chiarini F, Lonetti A, Buontempo F, Neri LM, McCubrey JA, Martelli AM. Autophagy in acute leukemias: a double-edged sword with important therapeutic implications. Biochim Biophys Acta. 2015; 1853:14-26.
50. Cerella C, Teiten MH, Radogna F, Dicato M, Diederich M. From nature to bedside: pro-survival and cell death mechanisms as therapeutic targets in cancer treatment. Biotechnol Adv. 2014; 32:1111-1122.
51. Abdel-Aziz AK, Shouman S, El-Demerdash E, Elgendy M, Abdel-Naim AB. Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries. Chem Biol Interact. 2014; 217:28-40.
52. Kampa-Schittenhelm KM, Heinrich MC, Akmut F, Rasp KH, Illing B, Dohner H, Dohner K, Schittenhelm MM. Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia. Mol Cancer. 2013; 12:46.
53. Shah AT, Demory Beckler M, Walsh AJ, Jones WP, Pohlmann PR, Skala MC. Optical metabolic imaging of treatment response in human head and neck squamous cell carcinoma. PloS one. 2014; 9:e90746.
54. Bodzin AS, Wei Z, Hurtt R, Gu T, Doria C. Gefitinib resistance in HCC mahlavu cells: upregulation of CD133 expression, activation of IGF-1R signaling pathway, and enhancement of IGF-1R nuclear translocation. J Cell Physiol. 2012; 227:2947-2952.
55. Gwak GY, Yoon JH, Kim KM, Lee HS, Chung JW, Gores GJ. Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression. J Hepatol. 2005; 42:358-364.
56. Kim KW, Bae SK, Lee OH, Bae MH, Lee MJ, Park BC. Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res. 1998; 58:348-351.
57. Mazure NM, Nguyen TL, Danan JL. Severe hypoxia specifically downregulates hepatocyte nuclear factor-4 gene expression in HepG2 human hepatoma cells. Tumour Biol. 2001; 22:310-317.
58. Baek JH, Jang JE, Kang CM, Chung HY, Kim ND, Kim KW. Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene. 2000; 19:4621-4631.
59. Mudie S, Bandarra D, Batie M, Biddlestone J, Moniz S, Ortmann B, Shmakova A, Rocha S. PITX1, a specificity determinant in the HIF-1alpha-mediated transcriptional response to hypoxia. Cell Cycle. 2014; 13:3878-3891.
60. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3:721-732.
61. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92:5510-5514.
62. Cui SY, Huang JY, Chen YT, Song HZ, Huang GC, De W, Wang R, Chen LB. The role of Aurora A in hypoxia-inducible factor 1alpha-promoting malignant phenotypes of hepatocelluar carcinoma. Cell Cycle. 2013; 12:2849-2866.
63. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004; 56:549-580.
64. Jung KH, Choi MJ, Hong S, Lee H, Hong SW, Zheng HM, Lee HS, Hong SS. HS-116, a novel phosphatidylinositol 3-kinase inhibitor induces apoptosis and suppresses angiogenesis of hepatocellular carcinoma through inhibition of the PI3K/AKT/mTOR pathway. Cancer Lett. 2012; 316:187-195.
65. Cikla-Suzgun P, Kaushik-Basu N, Basu A, Arora P, Talele TT, Durmaz I, Cetin-Atalay R, Kucukguzel SG. Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,4-triazoles. J Enzyme Inhib Med Chem. 2015; 2:1-8.
66. Tuncbilek M, Guven EB, Onder T, Cetin Atalay R. Synthesis of novel 6-(4-substituted piperazine-1-yl)-9-(beta-D-ribofuranosyl)purine derivatives, which lead to senescence-induced cell death in liver cancer cells. J Med Chem. 2012; 55:3058-3065.
67. Buontempo F, Ersahin T, Missiroli S, Senturk S, Etro D, Ozturk M, Capitani S, Cetin-Atalay R, Neri ML. Inhibition of Akt signaling in hepatoma cells induces apoptotic cell death independent of Akt activation status. Invest New Drugs. 2011; 29:1303-1313.
68. Valenti F, Fausti F, Biagioni F, Shay T, Fontemaggi G, Domany E, Yaffe MB, Strano S, Blandino G, Di Agostino S. Mutant p53 oncogenic functions are sustained by Plk2 kinase through an autoregulatory feedback loop. Cell Cycle. 2011; 10:4330-4340.
69. Chiarini F, Lonetti A, Teti G, Orsini E, Bressanin D, Cappellini A, Ricci F, Tazzari PL, Ognibene A, Falconi M, Pagliaro P, Iacobucci I, Martinelli G, et al. A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia. Oncotarget. 2012; 3:1615-1628.
70. Bressanin D, Evangelisti C, Ricci F, Tabellini G, Chiarini F, Tazzari PL, Melchionda F, Buontempo F, Pagliaro P, Pession A, McCubrey JA, Martelli AM. Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels. Oncotarget. 2012; 3:811-823.
71. Isayev O, Rausch V, Bauer N, Liu L, Fan P, Zhang Y, Gladkich J, Nwaeburu CC, Mattern J, Mollenhauer M, Ruckert F, Zach S, Haberkorn U, et al. Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine. Oncotarget. 2014; 5:5177-5189.
72. Sparta AM, Bressanin D, Chiarini F, Lonetti A, Cappellini A, Evangelisti C, Melchionda F, Pession A, Bertaina A, Locatelli F, McCubrey JA, Martelli AM. Therapeutic targeting of Polo-like kinase-1 and Aurora kinases in T-cell acute lymphoblastic leukemia. Cell Cycle. 2014; 13:2237-2247.