Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: Rationale and importance to inhibiting these pathways in human health

Oncotarget

Volumn 2, Issue 3, 2011, Pages 135-164

  Chappell, William H ^a   Steelman, Linda S ^a,b   Long, Jacquelyn M ^b   Kempf, Ruth C ^b   Abrams, Stephen L ^a   Franklin, Richard A ^a   Bäsecke, Jörg ^c   Stivala, Franca ^d   Donia, Marco ^d   Fagone, Paolo ^d   Malaponte, Graziella ^d   Mazzarino, Maria C ^d   Nicoletti, Ferdinando ^d   Libra, Massimo ^d   Maksimovic Ivanic, Danijela ^e   Mijatovic, Sanja ^e   Montalto, Giuseppe ^f   Cervello, Melchiorre ^g   Laidler, Piotr ^h   Milella, Michele ⁱ   Tafuri, Agostino ^j   Bonati, Antonio ^k   Evangelisti, Camilla ^l   Cocco, Lucio ^l   Martelli, Alberto M ^g,l   McCubrey, James A ^a   more..

^a EAST CAROLINA UNIVERSITY   (United States)

^b Department of Physics ^*  (United States)

^c UNIVERSITY OF GÖTTINGEN   (Germany)

^d UNIVERSITY OF CATANIA   (Italy)

^e UNIVERSITY OF BELGRADE   (Serbia)

^f UNIVERSITY OF PALERMO   (Italy)

^g CNR   (Italy)

^h JAGIELLONIAN UNIVERSITY MEDICAL COLLEGE   (Poland)

ⁱ REGINA ELENA NATIONAL CANCER INSTITUTE   (Italy)

^j SAPIENZA UNIVERSITY OF ROME   (Italy)

^k UNIVERSITY HOSPITAL OF PARMA   (Italy)

^l UNIVERSITY OF BOLOGNA   (Italy)

more..

Author keywords

Aging; Akt; Cancer stem cells; Combination therapy; Drug resistance; mTOR; Pi3K; Raf; Senescence; Targeted therapy

Indexed keywords

2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; CAPECITABINE; DOXORUBICIN; EVEROLIMUS; GEMCITABINE; K RAS PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE KINASE; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; N [3 (5 CHLORO 1H PYRROLO[2,3 B]PYRIDINE 3 CARBONYL) 2,4 DIFLUOROPHENYL]PROPANESULFONAMIDE; PACLITAXEL; PEMETREXED; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; RAF PROTEIN; RAPAMYCIN; RAS PROTEIN; RDEA 119; SELUMETINIB; SORAFENIB; TEMOZOLOMIDE; TEMSIROLIMUS; TRICIRIBINE; UNCLASSIFIED DRUG; VINBLASTINE; MTOR PROTEIN, HUMAN; PTEN PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE;

BREAST CANCER; CANCER CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER RADIOTHERAPY; CANCER RESISTANCE; CELL AGING; CELL PROLIFERATION; COLON CANCER; COLORECTAL CANCER; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG RESPONSE; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; ENZYME ACTIVATION; ENZYME INHIBITION; GENETIC SCREENING; HEMATOLOGIC MALIGNANCY; HUMAN; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; MELANOMA; MUTATOR GENE; NONHUMAN; ONCOGENE K RAS; PANCREAS CANCER; PIK3CA GENE; PROTEIN EXPRESSION; RADIOSENSITIZATION; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; UNSPECIFIED SIDE EFFECT; CELL TRANSFORMATION; DRUG ANTAGONISM; DRUG EFFECT; ENZYMOLOGY; METABOLISM; NEOPLASM; PATHOLOGY; TUMOR CELL LINE;

CELL LINE, TUMOR; CELL TRANSFORMATION, NEOPLASTIC; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; HUMANS; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASE KINASES; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; PTEN PHOSPHOHYDROLASE; RAF KINASES; RAS PROTEINS; TOR SERINE-THREONINE KINASES;

EID: 79959712087     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.240     Document Type: Review

References (273)

1. Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, et al. Contributions of the Raf/MEK/ ERK, PI3K/PTEN/Akt/mTOR and JAK/STAT pathways to leukemia. Leukemia 2008;22:686-707.
2. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, et al. Targeting Survival Cascades Induced by Activation of Raf/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 2008;22:708-22.
3. McCubrey JA, Milella M, Tafuri A, Martelli AM, Lunghi P, Bonati A, Cervello M, Lee JT, Steelman LS. Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors. Current Opinion in Investigational Drugs. 2008;9:614-30.
4. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, et al. Roles of the Raf/MEK/ ERK pathway in cell growth, malignant transformation and drug resistance. Biochem Biophys Acta 2007; 773:1263-84.
5. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006;439:358-62.
6. Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, Shigematsu H, Yamamoto H, Sawai A, Janakiraman M, Taylor BS, Pao W, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 2008; 68:9375-9383.
7. Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. Expert Rev Anticancer Ther 2009;9:739-45.
8. Huynh H, Soo KC, Chow PK, Tran E. Targeted inhibition of the extracellular signal-regulated kinases kinase pathway with AZD-6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther 2007;6:138-46.
9. Casar B, Pinto A, Crespo P. ERK dimmers and scaffold proteins: unexpected partners for a forgotten task. Cell Cycle 2009;8:1007-13.
10. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 2008;105:3041-6.
11. Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. BRAF silencing by short hairpin RNA or chemical blockade by PLX-4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res 2008;6:751-9.
12. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, Marais R. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010;140:209-21.
13. McCubrey JA, Steelman LS, Abrams SL, Chappell WH, Russo S, Ove R, Milella M, Tafuri A, Lunghi P, Bonati A, Stivala F, Nicoletti F, et al. Emerging MEK Inhibitors. Exp Opin Emerging Drugs 2010:15: 203-23.
14. Abrams SL, Steelman LS, Shelton JG, Wong ET, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA. The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 2010; 9:1781-91.
15. Iverson C, Larson G, Lai C, Yeh LT, Dadson C, Weingarten P, Appleby T, Vo T, Maderna A, Vernier JM, Hamatake R, Miner JN, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009; 69:6839-47.
16. McCubrey JA, Steelman LS, Kempf CR, Chappell WH, Abrams SL, Stivala F, Malaponte G, Nicoletti F, Libra M, Bäsecke J, Maksimovic-Ivanic D, Mijatovic S, et al. Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol 2011; In Press.
17. Delaney AM, Printen JA, Chen H, Fauman EB, Dudley DT. Identification of a novel mitogen-activated protein kinase kinase activation domain recognized by the inhibitor PD 184352. Mol Cell Biol 2002;22:7593-602.
18. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000;351:95-105.
19. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 2004;11:1192-97.
20. Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, et al. Targeting MEK induces myelomacell cytotoxicity and inhibits osteoclastogenesis. Blood 2007;110:1656-63.
21. Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogenactivated protein kinase kinase 1/ 2 inhibitor. Clin Cancer Res 2007;13:1576-83.
22. Wang D, Boerner SA, Winkler JD, LoRusso PM. Clinical experience of MEK inhibitors in cancer therapy. Biochem et Biophysica Acta 2007;1773:1248-55.
23. Davies BD, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD. AZD6244 (ARRY 142886) a potent inhibitor of mitogen-activated protein kinase/extracellular signal-related kinase kinase 1 /2 kinases: mechanism of action in vivo, pharmacokinetic/ pharmacodynamic relationship and potential for combination in preclinical models. Mol Cancer Ther. 2007;6:2209-19.
24. Friday BB, Yu C, Dy GK, Smith PD, Wang L, Thibodeau SN, Adjei AA. BRAF V600E disrupts AZD6244-induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and Raf proteins. Cancer Res 2008;68:6145-53.
25. Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol 2003;30:105-16.
26. Rinehart J, Adjei AA, LoRusso PM, Waterhouse D, Hecht JR, Natale RB, Hamid O, Varterasian M, Asbury P, Kaldjian EP, Gulyas S, Mitchell DY, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 2004;22:4456-62.
27. Sebolt-Leopold JS. Advances in the development of cancer therapeutics directed against the Ras-mitogen-activated protein kinase pathway. Clin Cancer Res 2008;14:3651-56.
28. Haura EB, Ricart AD, Larson TG, Stella PJ, Bazhenova L, Miller VA, Cohen RB, Eisenberg PD, Selaru P, Wilner KD, Gadgeel SM. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced nonsmall cell lung cancer. Clin Cancer Res. 2010;16:2450-7.
29. LoRusso PM, Krishnamurthi SS, Rinehart JJ, Nabell LM, Malburg L, Chapman PB, DePrimo SE, Bentivegna S, Wilner KD, Tan W, Ricart AD. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16:1924-37.
30. Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle 2009;8:1168-75.
31. McCubrey JA, Steelman LS, Abrams SL, Chappell WH, Russo S, Ove R, Milella M, Tafuri A, Lunghi P, Bonati A, Stivala F, Nicoletti F, et al. Emerging Raf Inhibitors. Exp Opin Emerging Drugs 2009;14:633-48.
32. Lee JT, Steelman LS, Chappell WH, McCubrey JA. Akt Inactivates ERK causing decreased response to chemotherapeutic drugs in advanced CaP cells. Cell Cycle 2008;7:631-6.
33. Wilhelm SM, Carter C, Tang LY, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, et al. BAY 43-9006 Exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Research 2004;64:7099-109.
34. Smalley KSM, Flaherty KT. Integrating BRAF/MEK inhibitors into combination therapy for melanoma. British J Can 2009;100:431-5.
35. Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon Met al. A new mouse model to explore the initiation, progression, and therapy of BRafV600E-induced lung tumors. Genes & Development 2007; 21: 379-84.
36. Cusimano A, Azzolina A, Iovanna JL, Bachvarov D, McCubrey JA, Alessandro ND, Monalto G, Cervello M. Novel combination of celecoxib and proteasome inhibitor MG132 in human hepatocellular carcinoma provides synergistic anti tumor effects. Cell Cycle 2010;9:1399-1410.
37. Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997;236:54-58.
38. Wiesenauer CA, Yip-Schneider MT, Wang Y, Schmidt CM. Multiple anticancer effects of blocking MEK-ERK signaling in hepatocellular carcinoma. J Am Coll Surg 2004;198:410-421.
39. Wentz SC, Wu H, Yip-Schneider MT, Hennig M, Klein PJ, Sebolt-Leopold, Schmidt CM.. Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGFalpha-transgenic mice. J Gastrointest Surg. 2008;12: 30-7.
40. Ricciardi MR, McQueen T, Chism D, Milella M, Estey E, Kaldjian E, Sebolt-Leopold J, Konopleva M, Andreeff M. Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia. Leukemia 2005;29:1543-9.
41. Gregorj C, Ricciardi MR, Petrucci MT, Scerpa MC, De Cave F, Fazi P, Vignetti M, Vitale A, Mancini M, Cimino G, Palmieri S, Di Raimondo F, et al. ERK1/2 phosphorylation is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia. Blood 2007;109:5473-6.
42. Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, Sellers WR, Lengauer C, Stegmeier F. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 2009;69:4286-93.
43. Hoeflich KP, O'Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, Januario T, Savage H, Punnoose E, Truong T, Zhou W, Berry L, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase in basal-like breast cancer models. Clin Cancer Res 2009;15:4649-64.
44. Chiarini F, Fala F, Tazzari PL, Ricci F, Astolfi A, Pession A, Pagliaro P, McCubrey JA, Martelli AM. Dual inhibition of class IA phosphatidylionsitol 3-kinase and mTOR as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res 2009;69:3520-8.
45. Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI, Hamilton AD, Polokoff M, Nicosia SV, Herlyn M, Sebti SM, Cheng JQ. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 2004;64:4394-9.
46. Fala F, Blalock WL, Tazzari P, Cappellini A, Chiarini F, Martinelli G, Tafuri A, McCubrey JA, Cocco L, Martelli AM. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T acute lymphoblastic leukemia. Molecular Pharmacology 2008;74:884-95.
47. Mandal M, Younes M, Swan EA, Jasser SA, Doan D, Yigitbasi O, McMurphey A, Ludwick J, El-Naggar AK, Bucana C, Mills GB, Myers JN. The Akt inhibitor KP372-1 inhibits proliferation and induces apoptosis and anoikis in squamous cell carcinoma of the head and neck. Oral Oncol 2006;42:430-9.
48. Tazzari PL, Tabellini G, Ricci F, Papa V, Bortul R, Chiarini F, Evangelisti C, Martinelli G, Bontadini A, Cocco L, McCubrey JA, Martelli AM. Synergistic proapoptotic activity of recombinant trail plus the akt inhibitor perifosine in acute myelogenous leukemia cells. Cancer Res 2008;68:9394-403.
49. Owonikoko T, Khuri ER, Ramalingam SS. Preoperative therapy for early-stage NSCLC: oppurtunities and challenges. Oncology 2009;23:886-892.
50. Tamburini J. Green AS. Chapuis N. Bardet V. Lacombe C. Mayeux P. Bouscary D. Targeting translation in acute myeloid leukemia: a new paradigm for therapy? Cell Cycle 2009;8:3893-9.
51. Donia M, McCubrey JA, Bendtzen K, Nicoletti F. Potential use of rapamycin in HIV infection. Br J Clin Pharmacol. 2010; 70:784-93.
52. Fouladi M, Laningham F, Wu J, O'Shaughnessy MA, Molina K, Broniscer A, Spunt SL, Luckett I, Stewart CF, Houghton PJ, Gilbertson RJ, Furman WL. Phase I study of Everolimus in pediatric patients with refractory solid tumors. JCO 2007;25:4806-12.
53. Krymskaya VP. Goncharova EA. PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects. Cell Cycle 2009;8:403-13.
54. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, et al. Identification and characterization of NVP-BEZ234, a new orally available dual PI3K/mTOR inhibitor with potent in vivo anti tumor activity. Mol Can Ther 2008;7:1851-63.
55. Garrett CR, Coppola D, Wenham RM, Cubitt CL, Neuger AM, Frost TJ, Lush RM, Sullivan DM, Cheng JQ, Sebti SM. Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest New Drugs. 2010 Jul 20.
56. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009;7:e38.154.
57. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS. An ATPcompetitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009;284:8023-32.
58. 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, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.
59. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34.
60. Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD, Robertson GP. Mutant V599E B-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res 2005;65:2412-21.
61. Sharma A, Tran MA, Liang S, Sharma AK, Amin S, Smith CD, Dong C, Robertson GP. Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-Raf signaling cascade effectively inhibits melanoma lung metastases. Cancer Res 2006;66:8200-09.
62. Tentler JJ, Nallapareddy S, Tan AC, Spreafico A, Pitts TM, Morelli MP, Selby HM, Kachaeva MI, Flanigan SA, Kulikowski GN, Leong S, Arcaroli JJ, et al. Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. Mol Cancer Ther. 2010; 3351-62.
63. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009 Mar 28;373(9669):1119-32.
64. Schumacher G, Oidtmann M, Rosewicz S, Langrehr J, Jonas S, Mueller AR, et al. Sirolimus inhibits growth of human hepatoma cells in contrast to tacrolimus, which promotes cell growth. Transplant Proc 2002; 34:1392-3.
65. Rizell M, Lindner P. Inhibition of mTOR suppresses experimental liver tumours. Anticancer Res 2005;25:789-93.
66. Semela D, Piguet AC, Kolev M, Schmitter K, Hlushchuk R, Djonov V, Stoupis C, Dufour JF. Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol 2007;46:840-8.
67. Rizell M, Andersson M, Cahlin C, Hafström L, Olausson M, Lindnér P. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 2008;13:66-70.
68. Sieghart W, Fuereder T, Schmid K, Cejka D, Werzowa J, Wrba F, Wang X, Gruber D, Rasoul-Rockenschaub S, Peck-Radosavljevic M, Wacheck V. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 2007;83:425-32.
69. Ribatti D, Nico B, Mangieri D, Longo V, Sansonno D, Vacca A, Dammacco F. In vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin. Histol Histopathol 2007;22:285-289.
70. Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, Doroshow JH. CCI-779 in metastatic melanoma: a phase II trial of the California cancer consortium. Cancer 2005;104:1045-8.
71. Molhoek KR, Brautigan DL, Slingluff CL Jr, Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor rapamycin. J Transl Med 2003;3:39.
72. Engleman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H104R murine lung cancers. Nat Med 2008;14:1351-6.
73. Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW, Tang ZY. Effects of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 2008;14:5124-30.
74. Legrier ME, Yang CP, Yan HG, Lopez-Barcons L, Keller SM, Perez-Soler R, Horwitz SB, McDaid HM. Targeting protein translation in human non-small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. Cancer Res 2007;67:11300-8.
75. Flaherty KT. Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res 2006;12:2366s-70s.
76. Andrieux LO, Fautrei A, Bessard A, Guillouzo A, Baffet G, Langouët S. GATA-1 is essential in EGF-meditated induction of nucleotide excision repair activity and ERCCI expression through ERK2 in human hepatoma cells. Cancer Res 2007;67:2114-23.
77. McDaid HM, Lopez-Barcons L, Grossman A, Lia M, Keller S, Pérez-Soler R, Horwitz SB. Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants. Cancer Res 2005;65:2854-60.
78. Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, Herlyn M, Smalley KS. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY 142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res 2008;14:230-9.
79. Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010; 304:2154-60.
80. Mabuchi S, Ohmichi M, Kimura A, Hisamoto K, Hayakawa J, Nishio Y, et al. Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J Biol Chem 2002;277:33490-500.
81. Brognard J, Dennis PA. Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants. Cell Death Differ 2002;9:893-904.
82. Aoki K, Ogawa T, Ito Y, Nakashima S. Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma. Oncol Rep 2004;11:375-9.
83. Rieber M, Rieber MS. Signalling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status. Int J Cancer 2006;118:1135-43.
84. Chung EJ, Brown AP, Asano H, Mandler M, Burgan WE, Carter D, Camphausen K, Citrin D. In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinases 1 /2 kinase. Clin Cancer Res 2009;15:3050-7.
85. Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan DE. Phosphatidylinositol 3-kinase/Akt signaling in the response to vascular endothelium to ionizing radiation. Cancer Res 2002;62:4671-77.
86. Shinohara ET, Cao C, Niermann K, Mu Y, Zeng F, Hallahan DE, Lu B. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 2005;24:5414-22.
87. Paglin S, Lee NY, Nakar C, Fitzgerald M, Plotkin J, Deuel B, Hackett N, McMahill M, Sphicas E, Lampen N, Yahalom J. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res 2005;65:11061-70.
88. Moretti L, Attia A, Kim KW, Lu B. Crosstalk between Bak/Bax and mTOR signaling regulates radiation induced autophagy. Autophagy 2007;3:142-4.
89. Misaghian N, Ligresti G, Steelman LS, Bertrand FE, Bäsecke J, Libra M, Nicoletti F, Stivala F, Milella M, Tafuri A, Cervello M, Martelli AM, et al. Targeting the leukemic stem cell-the holy grail of leukemia therapy. Leukemia 2009;23:25-42.
90. Montagut C, Sharma SV, Shioda T. McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Haber DA, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 2008;68:4853-61.
91. Smalley KS, Lioni M, Dalla Palma M, Xiao M, Desai B, Egyhazi S, Hansson J, Wu H, King AJ, Van Belle P, Elder DE, Flaherty KT, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600Emutated melanomas. Mol Cancer Ther 2008;7:2876-83.
92. Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010;120:2858-2866.
93. Mohseni M, Park BH. PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001. J Clin Invest 2010;120:2655-2658.
94. Zunder ER, Knight ZA, Houseman BT, Apsel B, Shokat KM. Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110α. Cancer Cell 2008;14:180-92.
95. Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV, Cheng JQ. Micro RNA expression profiling in human ovarian cancer: miR-274 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 2008;68:425-33.
96. Ouyang B, Knauf JA, Smith EP, Zhang L, Ramsey T, Yusuff N, Batt D, Fagin JA. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res 2006;12:1785-93.
97. Sathornsumetee S, Hjelmeland AB, Keir ST, McLendon RE, Batt D, Ramsey T, Yusuff N, Rasheed BK, Kieran MW, Laforme A, Bigner DD, Friedman HS, et al. AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma. Cancer Res 2006;66:8722-30.
98. Schwartz GK, Robertson S, Shen A. A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors. J Clin Oncol 2009;27:3513.
99. King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, Kumar R, Rusnak DW, Takle AK, Wilson DM, Hugger E, Wang L, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res 2006;66:11100-5.
100. Lefloch R. Pouyssegur J. Lenormand P. Total ERK1/2 activity regulates cell proliferation. Cell Cycle 2009;8:705-11.
101. Wang S. Koromilas AE. Stat1 is an inhibitor of Ras-MAPK signaling and Rho small GTPase expression with implications in the transcriptional signature of Ras transformed cells. Cell Cycle 2009;8:2070-9.
102. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 1995;92:7686-9.
103. Borysova MK, Cui Y, Snyder M, Guadagon TM. Knockdown of B-Raf impairs spindle formation and the mitotic checkpoint in human somatic cells. Cell Cycle 2008;7:2894-901.
104. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 1998;273:18623-32.
105. Jilaveanu LB, Zito CR, Aziz SA, Conrad PJ, Schmitz JC, Sznol M, Camp RL, Rimm DL, Kluger HM. C-Raf is associated with disease progression and cell proliferation in a subset of melanomas. Clin Cancer Res.2009; 5:5704-13.
106. Takle AK, Bamford MJ, Davies S, Davis RP, Dean DK, Gaiba A, Irving EA, King FD, Naylor A, Parr CA, Ray AM, Reith AD, et al. The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett 2008;18:4373-6.
107. Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994;269:5241-8.
108. Sampath D, Cortes J, Estrov Z, Du M, Shi Z, Andreeff M, Gandhi V, Plunkett W. Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood 2006;107:2517-24.
109. Stengel KR. Dean JL. Seeley SL. Mayhew CN. Knudsen ES. RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents. Cell Cycle 2008;7:1095-103.
110. Papa V, Tazzari PL, Chiarini F, Cappellini A, Ricci F, Billi AM, Evangelisti C, Ottaviani E, Martinelli G, Testoni N, McCubrey JA, Martelli AM. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia 2008;22:147-60.
111. Stauffer F, Maira SM, Furet P, García-Echeverría C. Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKBpathway. Bioorg Med Chem Lett 2008;18:1027-30.
112. Weisberg E, Banerji L, Wright RD, Barrett R, Ray A, Moreno D, Catley L, Jiang J, Hall-Meyers E, Sauveur-Michel M, Stone R, Galinsky I, et al. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells. Blood 2008;111:3723-34.
113. Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang SY, Robell K, Kahana JA, Geske RS, et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 2008;68:2366-74.
114. Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 2009;113:1723-9.
115. Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck SG, Travis R, Sausville EA, Houghton PJ. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001;7:1758-64.
116. Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007;109:3509-12.
117. Carracedo A. Baselga J. Pandolfi PP. Deconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors. Cell Cycle 2008;7:3805-9.
118. Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, Thomas D, Wierda W, Apostolidou E, Albitar M, O'Brien S, Andreeff M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006;12:5165-73.
119. Rizzieri DA, Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, Rivera VM, Albitar M, Bedrosian CL, Giles FJ. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008;14:2756-62.
120. Elit L. Drug evaluation: AP-23573--an mTOR inhibitor for the treatment of cancer. IDrugs. 2006;9:636-44.
121. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P, Venet M, Sanz G, Poignet H, Skrzat S, Devine A, Wouters W, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61:131-7.
122. Dy GK, Adjei AA. Farnesyltransferase inhibitors in breast cancer therapy. Cancer Invest 2002;20:30-7.
123. Chao WR, Amin K, Shi Y, Hobbs P, Tanabe M, Tanga M, Jong L, Collins N, Peters R, Laderoute K, Dinh D, Yean D, et al SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo. Angiogenesis. 2010 Nov 21.
124. Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S, Buckman BO, Lentz D, et al. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem 2005;280:19867-74.
125. Peifer C, Alessi DR. Small-molecule inhibitors of PDK1. ChemMedChem. 2008;3:1810-38.
126. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P. The selectivity of protein kinase inhibitors: a further update. Biochem J 2007;408:297-315.
127. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006;125:733-47.
128. Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA. A dual PI3 kinase/ mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006;9:341-9.
129. Prevo R, Deutsch E, Sampson O, Diplexcity J, Cengel K, Harper J, O'Neill P, McKenna WG, Patel S, Bernhard EJ. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res 2008;68:5915-23.
130. Zou ZQ, Zhang XH, Wang F, Shen QJ, Xu J, Zhang LN, Xing WH, Zhuo RJ, Li D. A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells. Int J Mol Med 2009;24:97-101.
131. Yacoub A, Park MA, Hanna D, Hong Y, Mitchell C, Pandya AP, Harada H, Powis G, Chen CS, Koumenis C, Grant S, Dent P. OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. Mol Pharmacol 2006;70:589-603.
132. Weng SC, Kashida Y, Kulp SK, Wang D, Brueggemeier RW, Shapiro CL, Chen CS. Sensitizing estrogen receptornegative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor. Mol Cancer Ther 2008;7:800-8.
133. Gao M, Yeh PY, Lu YS, Hsu CH, Chen KF, Lee WC, Feng WC, Chen CS, Kuo ML, Cheng AL. OSU-03012, a novel celecoxib derivative, induces reactive oxygen speciesrelated autophagy in hepatocellular carcinoma. Cancer Res 2008;68:9348-57.
134. Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, Abraham R, Kirkpatrick L, Powis G. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 2004;3:763-72.
135. Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 2007;6:2505-14.
136. Yu K, Lucas J, Zhu T, Zask A, Gaydos C, Toral-Barza L, Gu J, Li F, Chaudhary I, Cai P, Lotvin J, Petersen R, et al. PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors. Cancer Biol Ther 2005;4:538-45.
137. Zhu T, Gu J, Yu K, Lucas J, Cai P, Tsao R, Gong Y, Li F, Chaudhary I, Desai P, Ruppen M, Fawzi M, et al. Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft models. J Med Chem 2006;49:1373-8.
138. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 2000;6:909-19.
139. Stein RC. Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. Endocr Relat Cancer 2001;8:237-48.
140. Zeng Z, Samudio IJ, Zhang W, Estrov Z, Pelicano H, Harris D, Frolova O, Hail N Jr, Chen W, Kornblau SM, Huang P, Lu Y, et al. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. Cancer Res 2006;66:3737-46.
141. Koul D, Shen R, Bergh S, Sheng X, Shishodia S, Lafortune TA, Lu Y, de Groot JF, Mills GB, Yung WK. Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol Cancer Ther 2006;5:637-44.
142. Shapiro G, Kwak E, Baselga J. Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors. J Clin Oncol 2009;27:3500.
143. Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 2006;98:545-56.
144. Kong D, Okamura M, Yoshimi H, Yamori T. Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor. Eur J Cancer 2009;45:857-65.
145. Molckovsky A, Siu LL. First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting. J Hematol Oncol 2008;1:20.
146. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 2008;51:5522-32.
147. Raynaud FI, Eccles SA, Patel S, Alix S, Box G, Chuckowree I, Folkes A, Gowan S, De Haven Brandon A, Di Stefano F, Hayes A, Henley AT, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther 2009;8:1725-38.
148. Yao E, Zhou W, Lee-Hoeflich ST, Truong T, Haverty PM, Eastham-Anderson J, Lewin-Koh N, Gunter B, Belvin M, Murray LJ, Friedman LS, Sliwkowski MX, et al. Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin Cancer Res 2009;15:4147-56.
149. Serra V, Markman B, Scaltriti M, Eichorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, DiCosimo S, Maira M, Garcia-Echeverria C, 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.
150. Liu TJ, Koul D, LaFortune T, Tiao N, Shen RJ, Maira SM, Garcia-Echevrria C, Yung WK. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 2009;8:2204-10.
151. Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol 2008;1:27-36.
152. Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol 2009;145:569-80.
153. Marone R, Erhart D, Mertz AC, Bohnacker T, Schnell C, Cmilianovic V, Stauffer F, Garcia-Echeverria C, Giese B, Maira SM, Wymann MP. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol Cancer Res 2009;7:601-13.
154. Pomel V, Klicic J, Covini D, Church DD, Shaw JP, Roulin K, Burgat-Charvillon F, Valognes D, Camps M, Chabert C, Gillieron C, Françon B, et al. Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma. J Med Chem 2006;49:3857-71.
155. Takle AK, Brown MJ, Davies S, Dean DK, Francis G, Gaiba A, Hird AW, King FD, Lovell PJ, Naylor A, Reith AD, Steadman JG, et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett 2006;16:378-81.
156. Edwards LA, Verreault M, Thiessen B, Dragowska WH, Hu Y, Yeung JH, Dedhar S, Bally MB. Combined inhibition of the phosphatidylinositol 3-kinase/Akt and Ras/mitogenactivated protein kinase pathways results in synergistic effects in glioblastoma cells. Mol Cancer Ther 2006;5:645-54.
157. Hjelmeland AB, Lattimore KP, Fee BE, Shi Q, Wickman S, Keir ST, Hjelmeland MD, Batt D, Bigner DD, Friedman HS, Rich JN. The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion. Mol Cancer Ther 2007;6:2449-57.
158. Heim M, Sharifi M, Hilger RA, Scheulen ME, Seeber S, Strumberg D. Antitumor effect and potentiation or reduction in cytotoxic drug activity in human colon carcinoma cells by the Raf kinase inhibitor (RKI) BAY 43-9006. Int J Clin Pharmacol Ther 2003;41:616-7.
159. Wang X, Wang H, Xu L, Rozanski DJ, Sugawara T, Chan PH, Trzaskos JM, Feuerstein GZ. Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis. J Pharmacol Exp Ther 2003;304:172-8.
160. Sturgeon SA, Jones C, Angus JA, Wright CE. Advantages of a selective beta-isoform phosphoinositide 3-kinase antagonist, an anti-thrombotic agent devoid of other cardiovascular actions in the rat. Eur J Pharmacol 2008;587:209-15.
161. Kong D, Yamori T. Advances in development of phosphatidylinositol 3-kinase inhibitors. Curr Med Chem 2009;16:2839-54.
162. Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, Ogier-Denis E. Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem 2002;277:27613-21.
163. Kulp SK, Yang YT, Hung CC, Chen KF, Lai JP, Tseng PH, Fowble JW, Ward PJ, Chen CS. 3-phosphoinositidedependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res 2004;64:1444-51.
164. Shi Y, Liu X, Han EK, Guan R, Shoemaker AR, Oleksijew A, Woods KW, Fisher JP, Klinghofer V, Lasko L, McGonigal T, Li Q, et al. Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo. Neoplasia 2005;7:992-1000.
165. Mohapatra S, Chu B, Zhao X, Djeu J, Cheng JQ, Pledger WJ. Apoptosis of metastatic prostate cancer cells by a combination of cyclin-dependent kinase and AKT inhibitors. Int J Biochem Cell Biol 2009;41:595-602.
166. Evangelisti C, Ricci F, Tazzari P, Chiarini F, Battistelli M, Falcieri E, Ognibene A, Pagliaro P, Cocco L, McCubrey JA. Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia.: J of Cellular Physiology 2010;226:822-31.
167. Evangelisti C, Gaboardi GC, Billi AM, Ognibene A, Tazzori PL, McCubrey JA, Martelli AM. Identification of a functional nuclear export sequence in diacyl glycerol kinase delta. Cell Cycle 2010;9:384-8.
168. Martelli AM, Papa V, Tazzari PL, Evangelesti C, Chiarini C, Grimaldi C, Ricci F, Martinelli G, Ottaviani E, Pagliaro P, Horn S, Basecke J, et al. Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK2- and PP2-dependent mechanisms. Leukemia 2010;24:687-698.
169. Cappellini A, Chiarini F, Ognibene A, McCubrey JA, Martelli AM. The cyclin-dependent kinase inhibitor Roscovitine and the nucleoside analog sangivamycin induce apoptosis in caspase-3 deficient breast cancer cells independent of caspase mediated P-glycoprotein cleavage: Implications for therapy of drug resistant breast cancers. Cell Cycle 2009;8: 1421-5.
170. Chiarini F, Grimaldi C, Ricci F, Tazzari PL, Evangelisti C, Ognibene A, Battistelli M, Falcieri E, Melchionda F, Pession A, Pagliaro P, McCubrey JA, et al. Activity of the novel dual phosphatidylinositol 3-kinasse/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res 2010;70:8097-107.
171. Evangelisti C, Ricci F, Tazzari P, Tabellini G, Battistelli M, Falcieri E, Chiarini F, Bortul R, Melchionda F, Pagliaro P, Pesson A, McCubrey JA, Martelli AM. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell aculte lymphoblastic leukemia. Leukemia 2011; In Press.
172. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 2010;1:89-103.
173. Buitenhuis M. Coffer PJ. The role of the PI3K-PKB signaling module in regulation of hematopoiesis. Cell Cycle 2009;8:560-6.
174. Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, McCubrey JA. The emerging role of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cell biology. Cancers 2010;2:1576-1596.
175. Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Cappellini A, Ognibene A, McCubrey JA. The emerging role of the phosphatiylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogensis. Biochim Biophys Act 2010;1803:991-1002.
176. Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle. 2009; 8:3831-7.
177. Fujishita T, Aoki M, Taketo MM. The role of mTORC1 pathway in intestinal tumorigenesis. Cell Cycle 2009;8:3684-7.
178. Choo AY, Blenis J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 2009;8:567-72.
179. Gan B, DePinho RA. mTORC1 signaling governs hematopoietic stem cell quiescence. Cell Cycle 2009;8:1003-6.
180. Salmond RJ, Zamoyska R. How does the mammalian target of rapamycin (mTOR) influence CD8 T cell differentiation? Cell Cycle 2010; 9:2952-7.
181. Rao RR, Li Q, Shrikant PA. Fine-tuning CD8(+) T cell functional responses: mTOR acts as a rheostat for regulating CD8(+) T cell proliferation, survival and differentiation? Cell Cycle 2010;9:2996-3001.
182. Renner AG, Creancier L, Dos Santos C, Fialin C, Recher C, Bailly C, Kruczynski A, Payrastre B, Manenti S. A functional link between polo-like kinase 1 and the mammalian target-of-rapamycin pathway? Cell Cycle 2010;9:1690-6.
183. Tsang CK, Liu H, Zheng XF. mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes. Cell Cycle 2010; 9:953-7.
184. Kim E, Guan KL. RAG GTPases in nutrient-mediated TOR signaling pathway. Cell Cycle 2009;8:1014-8.
185. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ. PTEN-dependence distinguishes haematopoietic stem cells from leukemia-initating cells. Nature 2006;441:475-8.
186. Blagosklonny MV. Cancer stem cell and cancer stemloids: from biology to therapy. Cancer Biology & Therapy 2007;6:1684-90.
187. Ligresti G, Militello L, Steelman LS, Cavallaro A, Basile F, Nicoletti F, Stivala F, McCubrey JA, Libra M. PIK3CA mutations in human solid tumors. Cell Cycle 2009:8: 1352-8.
188. Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007;1:101-12.
189. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi PP. PML targeting eradicates quiescent leukaemiainitiating cells. Nature 2008;453:1072-79.
190. Ito K, Bernardi R, Pandolfi PP. A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell. Genes Devel 2009;19:51-9.
191. McCubrey JA, Abrams SL, Stadelman K, Chappell WH, Lahair M, Ferland RA, Steelman LS. Targeting signal transduction pathways to eliminate chemotherapeutic drug resistance and cancer stem cells. Advan in Enzy Regul 2010;50:285-307.
192. McCubrey JA, Chappell WH, Abrams SL, Franklin RA, Long JM, Sattler JA, Kempf CR, Laidler P, Steelman LS. Targeting the cancer initiating cells: the Achilles' heel of cancer. Adv Enzyme Regul 2011;51.
193. Lu KH, Chen YW, Tsai PH, Tsai ML, Lee YY, Chiang CY, Kao CL, Chiou SH, Ku HH, Lin CH, Chen YJ. Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells. Childs Nerv Syst. 2009; 25:543-50.
194. Shankar S, Nall D, Tang SN, Meeker D, Passarini J, Sharma J, Srivastava RK. Resveratrol inhibits pancreatic cancer stem cell characteristics in human and kras transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One. 2011;6(1):e16530.
195. Castellano G, Torrisi E, Ligresti G, Malaponte G, Militello L, Russo A, McCubrey J, Canevari S, Libra M. The involvement of the transcription factor yin yang 1 in cancer development and progression. Cell Cycle 2009: 8:1367-72.
196. Gil D, Ciolczyk-Wierzbicka D, Dulinska-Litewka J, Zwawa K, McCubrey JA, Laidler P. The mechanism of contribution of integrin linked kinase (ILK) to epithelial mesenchymal transition. Adv Enzyme Regul 2011;51
197. Lee JY, Nakada D, Yilmaz OH, Tothova Z, Joseph NM, Lim MS, Gilliland DG, Morrison SJ. mTOR Activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell 2010;7:593-605.
198. Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 2008;27:1749-1758.
199. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 2008;205:2397-2408.
200. Zimmerman EI, Dollins CM, Crawford M, Grant S, Nana-Sinkam SP, Richards KL, Hammond SM, Graves LM. Lyn kinase-dependent regulation of miR181 and myeloid cell leukemia-1 expression: implications for drug resistance in myelogenous leukemia. Mol Pharmacol 2010;78:811-17.
201. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 2008;22:436-48.
202. Charles N, Holland EC. The perivascular niche microenvironment in brain tumor progression. Cell Cycle 2010;9:3012-21.
203. Heuser M, Humphries RK. Biologic and experimental variation of measured cancer stem cells. Cell Cycle 2010;9:909-12.
204. Liu Y, Dean DC. Tumor initiation via loss of cell contact inhibition versus Ras mutation: do all roads lead to EMT? Cell Cycle 2010;9:897-900.
205. Hussenet T, Dembele D, Martinet N, Vignaud JM, du Manoir S. An adult tissue-specific stem cell molecular phenotype is activated in epithelial cancer stem cells and correlated to patient outcome. Cell Cycle 2010;9:321-7.
206. Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 2009;8:3274-84.
207. Hazlehurst LA, Argilagos RF, Dalton WS. Beta1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells. Br J Haematol 2007;136:269-75.
208. Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 2008;14:2519-26.
209. Nair RR, Tolentino J, Hazlehurst LA. The bone marrow microenvironment as a sanctuary for minimal residual disease in CML. Biochem Pharmacol 2010;80:602-12.
210. Podar K, Chauhan D, Anderson KC. Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 2009;23:10-24.
211. Stuart SA, Minami Y, Wang JY. The CML stem cell: evolution of the progenitor. Cell Cycle 2009;8:1338-43.
212. Chapuis N, Tamburini J, Green AS, Willems L, Bardet V, Park S, Lacombe C, Mayeux P, Bouscary D. Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies. Leukemia 2010;24:1686-99.
213. Chen Y, Li D, Li S. The Alox5 gene is a novel therapeutic target in cancer stem cells of chronic myeloid leukemia. Cell Cycle 2009;8:3488-92.
214. Steelman LS, Abrams SL, Shelton JG, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA. Dominant roles of the Raf/ MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs. Cell Cycle 2010;9:1629-38.
215. Abrams SL, Steelman LS, Shelton JG, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA. Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy. Cell Cycle 2010;9:1839-46.
216. Zhou J, Wulkuhle J, Zhang H, Gu P, Yang Y, Deng J, Margolick JB, Liotta LA, Petricoin E 3rd, Zhang Y. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA 2007;104:16158-63.
217. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008;100: 672-679.
218. Shafee N, Smith CR, Wei S, Kim Y, Mills GB, Hortobagyi GN, Stanbridge EJ, Lee EY. Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Cancer Res 2008;68:3243-50.
219. Ginestier C, Wicinski J, Cervera N, Monville F, Finetti P, Bertucci F, Wicha MS, Birnbaum D. Charafe-Jauffret, Emmanuelle. Retinoid signaling regulates breast cancer stem cell differentiation. Cell Cycle 2009;8:3297-302.
220. Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, Clouthier SG, Wicha MS. Regulation of mammary stem/progenitor cells by PTEN/Akt/b-catenin signaling. PLOS Biology 2009;7:e1000121.
221. Vicente-Duenas C, Perez-Caro M, Abollo-Jimenez F, Cobaleda C, Sanchez-Garcia, I. Stem-cell driven cancer: "hands-off" regulation of cancer development. Cell Cycle. 2009;8:1314-8.
222. Borovski T, Vermeulen L, Sprick MR, Medema JP. One renegade cancer stem cell? Cell Cycle 2009;8:803-8.
223. Peter ME. Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle 2009; 8:843-52.
224. Mathew G, Timm EA Jr, Sotomayor P, Godoy A, Montecinos VP, Smith GJ, Huss WJ. ABCG2-mediated DyeCycle Violet efflux defined side population in benign and malignant prostate. Cell Cycle 2009;8:1053-61.
225. Alvero AB, Chen R, Fu H-H, Montagna M, Schwartz PE, Rutherford T, Silasi D-A, Steffensen KD, Waldstrom M, Visintin I, Mor G. Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 2009;8:158-66.
226. Bleau A-M, Huse JT, Holland EC. The ABCG2 resistance network of glioblastoma. Cell Cycle 2009;8:2936-44.
227. Sabisz M, Skladonowski A. Cancer stem cells and escape from drug-induced premature senescence in human lung tumor cells: implications for drug resistance and in vitro drug screening models. Cell Cycle 2009;8:3208-17.
228. Garinis GA, Schumacher B. Transcription-blocking DNA damage in aging and longevity. Cell Cycle 2009;8:2134-5.
229. Bazarov AV, Hines WC, Mukhopadhyay R, Beliveau A, Meldoyev S, Zaslavsky Y, Yaswen P. Telomerase activation by c-Myc in human mammary epithelial cells requires additional genomic changes. Cell Cycle 2009;8:3373-8.
230. Mele DA, Bista P, Baez DV, Huber BT. Dipeptidylpeptidase 2 is an essential survival factor in the regulation of cell quiescence. Cell Cycle 2009;8:2425-34.
231. Perucca P, Cazzalini O, Madine M, Savio M, Laskey RA, Vannini V, Prosperi E, Stivala LA. Loss of p21 CDKN1A impairs entry to quiescence and activates a DNA damage response in normal fibroblasts induced to quiescence. Cell Cycle 2009;8:105-14.
232. Liu Y, Elf SE, Asai T, Miyata Y, Liu Y, Sashida G, Huang G, Di Giandomenico S, Koff A, Nimer SD. The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior. Cell Cycle 2009; 8:3120-4.
233. Korotchkina LG, Demidenko ZN, Gudkov AV, Blagosklonny MV. Cellular quiescence caused by the Mdm2 inhibitor nutlin-3A. Cell Cycle 2009; 8:3777-81.
234. Steelman LS, McCubrey JA. Intriguing novel abilities of Nutlin-3A: induction of cellular quiesence as opposed to cellular senescence-implications for chemotherapy. Cell Cycle 2009;8:3634-5.
235. Jung-Hynes B, Ahmad N. Role of p53 in the antiproliferative effects of Sirt1 inhibition in prostate cancer cells. Cell Cycle 2009;8:1478-83.
236. Nelson G, Buhmann M, von Zglinicki T. DNA damage foci in mitosis are devoid of p53BP. Cell Cycle 2009;8:3379-83.
237. Li L, Borodyansky L, Yang Y. Genomic instability en route to and from cancer stem cells. Cell Cycle 2009;8:1000-2.
238. Burdach S, Plehm S, Unland R, Dirksen U, Borkhardt A, Staege MS, Muller-Tidow C, Richter GHS. Epigenetic maintenance of stemness and malignancy in peripheral neuroectodermal tumors by EZH2. Cell Cycle 2009;8:1991-6.
239. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV, Blagosklonny MV. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging 2010;2:344-52.
240. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci USA 2010;107:9660-4.
241. Pospelova TV, Demidenko ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV. Pseudo-DNA damage response in senescent cells. Cell Cycle 2009; 8:4112-8.
242. Matthew EM, Hart LS, Astrinidis A, Navaraj A, Dolloff NG, Dicker DT, Henske EP, El-Deiry WS. The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions. Cell Cycle 2009;8:4168-75.
243. Blagosklonny MV. Program-like aging and mitochondria: instead of random damage by free radicals. J Cell Biochemistry 2007;102:1389-99.
244. Blagosklonny MV, Campisi J, Sinclair DA. Aging: past, present and future. Aging 2009;1:1-5.
245. Blagosklonny MV. Paradoxes of aging. Cell Cycle 2007;6:2997-3003.
246. Blagosklonny MV. Campisi J. Cancer and aging: more puzzles, more promises. Cell Cycle. 2008;7:2615-18.
247. Blagosklonny MV, Hall MN. Growth and aging: a common molecular mechanism. Aging 2009;1:357-62.
248. Blagosklonny MV. Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmalogical rejuvenation of aging stem cells. Rejuvenation Res 2008;11:801-8.
249. Blagosklonny MV. Aging: ROS or TOR. Cell Cycle 2008;7:3344-54.
250. Blagosklonny MV. TOR-driven aging: speeding car without brakes. Cell Cycle 2009; 8:4055-9.
251. Demidenko ZN, Shtutman M, Blagosklonny MV. Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence. Cell Cycle 2009;8:1896-900.
252. Demidenko ZN, Blagosklonny MV. At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence. Cell Cycle 2009;8:1901-4.
253. de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ, de Bruin A, Dansen TB, Marais R, Brenkman AB, Burgering BM. Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Research 2010;70:8526-36.
254. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle 2008;7:3355-61.
255. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle 2009; 8:1888-95.
256. Blagosklonny MV. Aging-suppressants: Cellular senescence (hyperactivation) and its pharmacologic decleration. Cell Cycle 2009; 8:1883-7.
257. Blagosklonny, Mikhail V. Inhibition of S6K by resveratrol: in search of the purpose.WAging 2009;1:511-4.
258. Heeren G, Rinnerthaler M, Laun P, von Seyerl P, Kossler S, Klinger H, Hager M, Bogengruber E, Jarolim S, Simon-Nobbe B, Schuller C, Carmona-Gutierrez D, et al. The mitochondrial ribosomal protein of the large subunit, Afo1p, determines cellular longevity through mitochondrial back-signaling via TOR1. Aging 2009; 1:622-36.
259. Armour SM, Baur JA, Hsieh SN, Land-Bracha A, Thomas SM, Sinclair DA. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging 2009;1:515-28.
260. Jin J. Wang GL. Salisbury E. Timchenko L. Timchenko NA. GSK3beta-cyclin D3-CUGBP1-eIF2 pathway in aging and in myotonic dystrophy. Cell Cycle 2009;8:2356-9.
261. Sang L, Coller HA. Fear of commitment: Hes1 protects quiescent fibroblasts from irreversible cellular fates. Cell Cycle 2009;8:2161-7.
262. Gems D, Doonan R. Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 2009;8:1681-7.
263. Goldberg AA, Richard VR, Kyryakov P, Bourque SD. Beach A, Burstein MT, Glebov A, Koupaki O, Boukh-Viner T, Gregg C, Juneau M, English AM, et al.. Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes. Aging 2010;2:393-414.
264. Blagosklonny MV. Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives. Aging 2010;2:265-73.
265. Blagosklonny MV. Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slowaging" hypothesis. Aging 2010;2:177-82.
266. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging 2009;1:281-8.
267. Demidenko ZN, Blagosklonny MV. Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential. Aging 2009;1:1008-16.
268. Simpson SJ, Raubenheimer D. Macronutrient balance and lifespan. Aging 2009;1:875-80.
269. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. American J Path 2010;176:2092-7.
270. Blagosklonny MV. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Discovery Today 2007;12:218-24.
271. Anisimov VN. Berstein LM. Egormin PA. Piskunova TS. Popovich IG. Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 2008;7:2769-73.
272. Guenther GG, Edinger AL. A new take on ceramide: starve cells by cutting off the nutrient supply. Cell Cycle 2009;8:1122-6.
273. Blagosklonny MV. Calorie restriction: decelerating mTORdriven aging from cells to organisms (including humans). Cell Cycle 2010;9:683-8.