PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways

Anticancer Research

Volumn 30, Issue 12, 2010, Pages 4951-4958

  Gedaly, Roberto ^a   Angulo, Paul ^a   Hundley, Jonathan ^a   Daily, Michael F ^a   Chen, Changguo ^a   Koch, Alvaro ^a   Mark Evers, B ^a,b  

^a UNIVERSITY OF KENTUCKY   (United States)

^b UNIVERSITY OF KENTUCKY   (United States)

Author keywords

Epidermal growth factor; MTOR complex 1; MTOR complex 2; Negative feedback loop; PI 103; PI13 AKT mTOR; Rapamycin; Ras Raf MAPK; Sora fenib

Indexed keywords

2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; EPIDERMAL GROWTH FACTOR; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN KINASE B; RAF PROTEIN; RAS PROTEIN; SORAFENIB; THYMIDINE;

ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EFFECT; DRUG INHIBITION; DRUG MECHANISM; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; LIVER CELL CARCINOMA; PRIORITY JOURNAL; WESTERN BLOTTING;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BENZENESULFONATES; CARCINOMA, HEPATOCELLULAR; CELL GROWTH PROCESSES; CELL LINE, TUMOR; DOSE-RESPONSE RELATIONSHIP, DRUG; EPIDERMAL GROWTH FACTOR; FURANS; HUMANS; LIVER NEOPLASMS; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASES; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; PYRIDINES; PYRIMIDINES; RAF KINASES; RAS PROTEINS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 78751513089     PISSN: 02507005     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (20)

1. Llovet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet 362: 1907-1917,2003.
2. Befeler AS, Hayashi PH and Di Bisceglie AM: Liver transplantation for hepatocellular carcinoma. Gastroenterology 128: 1752-1764, 2005.
3. Strumberg D: Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Bare) 41: 773-784, 2005. (Pubitemid 43333354)
4. Minguez B, Tovar V, Chiang D, Villanueva A and Llovet JM: Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 25: 186-194, 2009.
5. Chaparro M, Gonzalez ML, Trapero-Marugan M, Medina J and Moreno-Otero R: Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents. Aliment Pharmacol Ther 28: 1269-1277, 2008.
6. 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, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D and Bruix J: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359: 378-390, 2008.
7. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, Chow P, Ong HS, Chung A and Soo KC: Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med 13: 2673-2683, 2009.
8. Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM and Weiss WA: A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9: 341-349, 2006. (Pubitemid 43668732)
9. Kojima K, Shimanuki M, Shikami M, Samudio IJ, Ruvolo V, Corn P, Hanaoka N, Konopleva M, Andreeff M and Nakakuma H: The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 22: 1728-1736, 2008.
10. Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, Savic R, Hoshida Y, Lim KH, Melgar-Lesmes P, Yea S, Peix J, Deniz K, Fiel MI, Thung S, Alsinet C, Tovar V, Mazzaferro V, Bruix J, Roayaie S, Schwartz M, Friedman SL and Llovet JM: Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 51: 725-733, 2009.
11. Llovet JM and Bruix J: Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48: 1312-1327, 2008.
12. Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, Zhang WG, Mahoney R, Gaydos C, Tardio L, Kim SK, Conant R, Curran K, Kaplan J, Verheijen J, yral-Kaloustian S, Mansour TS, Abraham RT, Zask A and Gibbons JJ: Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 70: 621-631, 2010.
13. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J and Pandolfi PP: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118: 3065-3074, 2008.
14. Nakanishi K, Fujimoto J, Ueki T, Kishimoto K, HashimotoTamaoki T, Furuyama J, Itoh T, Sasaki Y and Okamoto E: Hepatocyte growth factor promotes migration of human hepatocellular carcinoma via phosphatidylinositol 3-kinase. Clin Exp Metastasis 17: 507-514, 1999.
15. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, Roayaie S, Minguez B, Sole M, Battiston C, Van LS, Fiel MI, Di FA, Hoshida Y, Yea S, Toffanin S, Ramos A, Martignetti JA, Mazzaferro V, Bruix J, Waxman S, Schwartz M, Meyerson M, Friedman SL, Llovet JM: Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135: 1972-83, 1983, 2008.
16. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL and Sabatini DM: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159-168, 2006.
17. Sarbassov DD, Guertin DA, Ali SM and Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098-1101, 2005.
18. Zou CY, Smith KD, Zhu QS, Liu J and McCutcheon IE: Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor. Mol Cancer Ther 8: 1157-1168, 2009.
19. Wan X, Harkavy B, Shen N, Grohar P and Helman LJ: Rapamycin induces feedback activation of Akt signaling through an IGF-IR-dependent mechanism. Oncogene 26: 1932-1940, 2007.
20. Fan QW, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM and Weiss WA: A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67: 7960-7965, 2007.