Synthetic oleanane triterpenoids: Multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease

Pharmacological Reviews

Volumn 64, Issue 4, 2012, Pages 972-1003

  Liby, Karen T ^a   Sporn, Michael B ^a  

^a DARTMOUTH MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BARDOXOLONE; EPIDERMAL GROWTH FACTOR RECEPTOR 2; IMATINIB; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; JANUS KINASE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; NITRILOTRIACETATE IRON; PENTACYCLIC TRITERPENE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN INHIBITOR OF ACTIVATED STAT; SYNTHETIC OLEANANE TRITERPENOID; TRANSFORMING GROWTH FACTOR BETA; TRITERPENOID; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; AUTOIMMUNE DISEASE; CANCER INHIBITION; CANCER PREVENTION; CARDIOVASCULAR DISEASE; CELL DIFFERENTIATION; CELL PROLIFERATION; CHRONIC DISEASE; DIGESTIVE SYSTEM DISEASE; DRUG MECHANISM; EYE DISEASE; HUMAN; IN VITRO STUDY; INFLAMMATORY DISEASE; KIDNEY DISEASE; LIVER DISEASE; LOW DRUG DOSE; LUNG DISEASE; METABOLIC DISORDER; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PRIORITY JOURNAL; REVIEW;

ANIMALS; ANTI-INFLAMMATORY AGENTS; APOPTOSIS; CHRONIC DISEASE; HUMANS; OLEANOLIC ACID; OXIDATIVE STRESS;

EID: 84867055462     PISSN: 00316997     EISSN: 15210081     Source Type: Journal    
DOI: 10.1124/pr.111.004846     Document Type: Review

References (299)

1. Abel EL, Bubel JD, Simper MS, Powell L, McClellan SA, Andreeff M, MacLeod MC, and DiGiovanni J (2011) Protection against 2-chloroethyl ethyl sulfide (CEES)- induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway. Toxicol Appl Pharmacol 255:176-183.
2. Abraham NG, Cao J, Sacerdoti D, Li X, and Drummond G (2009) Heme oxygenase: the key to renal function regulation. Am J Physiol Renal Physiol 297:F1137-F1152.
3. Acharya A, Das I, Chandhok D, and Saha T (2010) Redox regulation in cancer: a double-edged sword with therapeutic potential. Oxid Med Cell Longev 3:23-34.
4. Ahmad R, Liu S, Weisberg E, Nelson E, Galinsky I, Meyer C, Kufe D, Kharbanda S, and Stone R (2010) Combining the FLT3 inhibitor PKC412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation. Mol Cancer Res 8:986-993.
5. Ahmad R, Raina D, Meyer C, Kharbanda S, and Kufe D (2006) Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem 281:35764-35769.
6. Ahmad R, Raina D, Meyer C, and Kufe D (2008) Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. Cancer Res 68:2920-2926.
7. Alabran JL, Cheuk A, Liby K, Sporn M, Khan J, Letterio J, and Leskov KS (2008) Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO. Cancer Biol Ther 7:709-717.
8. Aleksunes LM, Goedken MJ, Rockwell CE, Thomale J, Manautou JE, and Klaassen CD (2010) Transcriptional regulation of renal cytoprotective genes by Nrf2 and its potential use as a therapeutic target to mitigate cisplatin-induced nephrotoxicity. J Pharmacol Exp Ther 335:2-12.
9. Ames E, Harouna S, Meyer C, Welniak LA, and Murphy WJ (2012) The triterpenoid CDDO-Me promotes hematopoietic progenitor expansion and myelopoiesis in mice. Biol Blood Marrow Transplant 18:396-405.
10. Auletta JJ, Alabran JL, Kim BG, Meyer CJ, and Letterio JJ (2010) The synthetic triterpenoid, CDDO-Me, modulates the proinflammatory response to in vivo lipopolysaccharide challenge. J Interferon Cytokine Res 30:497-508.
11. Balkwill FR and Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22:33-40
12. Barabási AL (2007) Network medicine-from obesity to the "diseasome". N Engl J Med 357:404-407.
13. Barabási AL, Gulbahce N, and Loscalzo J (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12:56-68.
14. Baselga J (2010) Treatment of HER2-overexpressing breast cancer. Ann Oncol 21 (Suppl 7):vii36-vii40.
15. Bauer AK, Cho HY, Miller-Degraff L, Walker C, Helms K, Fostel J, Yamamoto M, and Kleeberger SR (2011) Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice. PLoS One 6:e26590.
16. Ben-Neriah Y and Karin M (2011) Inflammation meets cancer, with NF-_B as the matchmaker. Nat Immunol 12:715-723.
17. Benjamin D, Colombi M, Moroni C, and Hall MN (2011) Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10:868-880.
18. Bernstein SH, Venkatesh S, Li M, Lee J, Lu B, Hilchey SP, Morse KM, Metcalfe HM, Skalska J, Andreeff M, et al. (2012) The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood 119:3321-3329.
19. Bierie B and Moses HL (2010) Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev 21:49-59.
20. Brookes PS, Morse K, Ray D, Tompkins A, Young SM, Hilchey S, Salim S, Konopleva M, Andreeff M, Phipps R, et al. (2007) The triterpenoid 2-cyano-3,12-dioxooleana- 1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore. Cancer Res 67:1793-1802.
21. Brown KK and Hampton MB (2011) Biological targets of isothiocyanates. Biochim Biophys Acta 1810:888-894.
22. Bunney TD and Katan M (2010) Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat Rev Cancer 10:342-352.
23. Burton NC, Kensler TW, and Guilarte TR (2006) In vivo modulation of the Parkinsonian phenotype by Nrf2. Neurotoxicology 27:1094-1100.
24. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, and Johnson JA (2009) The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 11:497-508.
25. Cano M, Thimmalappula R, Fujihara M, Nagai N, Sporn M, Wang AL, Neufeld AH, Biswal S, and Handa JT (2010) Cigarette smoking, oxidative stress, the antioxidant response through Nrf2 signaling, and Age-related Macular Degeneration. Vision Res 50:652-664.
26. Carmeliet P and Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10:417-427.
27. Chauhan D, Li G, Podar K, Hideshima T, Shringarpure R, Catley L, Mitsiades C, Munshi N, Tai YT, Suh N, et al. (2004) The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Blood 103:3158-3166.
28. Cheung KL and Kong AN (2010) Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention. Aaps J 12:87-97.
29. Chintharlapalli S, Papineni S, Konopleva M, Andreef M, Samudio I, and Safe S (2005) 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways. Mol Pharmacol 68:119-128.
30. Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, and Kleeberger SR (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 26:175-182.
31. Cho HY and Kleeberger SR (2010) Nrf2 protects against airway disorders. Toxicol Appl Pharmacol 244:43-56.
32. Cho HY, Reddy SP, Yamamoto M, and Kleeberger SR (2004) The transcription factor NRF2 protects against pulmonary fibrosis. Faseb J 18:1258-1260.
33. Clarke JD, Dashwood RH, and Ho E (2008) Multi-targeted prevention of cancer by sulforaphane. Cancer Lett 269:291-304.
34. Couch RD, Browning RG, Honda T, Gribble GW, Wright DL, Sporn MB, and Anderson AC (2005) Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: implications for a molecular mechanism of action. Bioorg Med Chem Lett 15:2215-2219.
35. Couch RD, Ganem NJ, Zhou M, Popov VM, Honda T, Veenstra TD, Sporn MB, and Anderson AC (2006) 2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oic acid disrupts microtubule polymerization: a possible mechanism contributing to apoptosis. Mol Pharmacol 69:1158-1165.
36. Daroczi B, Kari G, Ren Q, Dicker AP, and Rodeck U (2009) Nuclear factor kappaB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos. Mol Cancer Ther 8:2625-2634.
37. Dauer DJ, Ferraro B, Song L, Yu B, Mora L, Buettner R, Enkemann S, Jove R, and Haura EB (2005) Stat3 regulates genes common to both wound healing and cancer. Oncogene 24:3397-3408.
38. Deeb D, Gao X, Arbab AS, Barton K, Dulchavsky SA, and Gautam SC (2010a) CDDO-Me: a novel synthetic triterpenoid for the treatment of pancreatic cancer. Cancers 2:1779-1793.
39. Deeb D, Gao X, Dulchavsky SA, and Gautam SC (2007) CDDO-me induces apoptosis and inhibits Akt, mTOR and NF-kappaB signaling proteins in prostate cancer cells. Anticancer Res 27:3035-3044.
40. Deeb D, Gao X, Dulchavsky SA, and Gautam SC (2008) CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kappaB and NFkappaB- regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. J Exp Ther Oncol 7:31-39.
41. Deeb D, Gao X, Jiang H, Dulchavsky SA, and Gautam SC (2009) Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro-survival Akt and mTOR. Prostate 69:851-860.
42. Deeb D, Gao X, Jiang H, Janic B, Arbab AS, Rojanasakul Y, Dulchavsky SA, and Gautam SC (2010b) Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. Biochem Pharmacol 79:350-360.
43. Deeb D, Gao X, Liu Y, Jiang D, Divine GW, Arbab AS, Dulchavsky SA, and Gautam SC (2011) Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate cancer in TRAMP mice by inhibiting survival signaling. Carcinogenesis 32:757-764.
44. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, et al. (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106-109.
45. Dezube BJ, Kurzrock R, Eder JP, Supko JG, Meyer CJ, Camacho LH, Andreeff M, Konopleva M, Lescale-Matys L, and Hong D (2007) Interim results of a phase I trial with a novel orally administered synthetic triterpenoid RTA 402 (CDDO-Me) in patients with solid tumors and lymphoid malignancies (Abstract). J Clin Oncol 25 (18 Suppl):14101.
46. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, and Talalay P (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99:11908-11913.
47. Dinkova-Kostova AT, Jenkins SN, Wehage SL, Huso DL, Benedict AL, Stephenson KK, Fahey JW, Liu H, Liby KT, Honda T, et al. (2008) A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UVirradiated mice. Biochem Biophys Res Commun 367:859-865.
48. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, et al. (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102:4584-4589.
49. Doulias PT, Greene JL, Greco TM, Tenopoulou M, Seeholzer SH, Dunbrack RL, and Ischiropoulos H (2010) Structural profiling of endogenous S-nitrosocysteine residues reveals unique features that accommodate diverse mechanisms for protein S-nitrosylation. Proc Natl Acad Sci USA 107:16958-16963.
50. Duan Z, Ames RY, Ryan M, Hornicek FJ, Mankin H, and Seiden MV (2009) CDDOMe, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol 63: 681-689.
51. Dumont M, Wille E, Calingasan NY, Tampellini D, Williams C, Gouras GK, Liby K, Sporn M, Nathan C, Flint Beal M, et al. (2009) Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer's disease. J Neurochem 109:502-512.
52. Dvorak HF, Weaver VM, Tlsty TD, and Bergers G (2011) Tumor microenvironment and progression. J Surg Oncol 103:468-474.
53. Elliott S, Hays E, Mayor M, Sporn M, and Vincenti M (2003) The triterpenoid CDDO inhibits expression of matrix metalloproteinase-1, matrix metalloproteinase-13 and Bcl-3 in primary human chondrocytes. Arthritis Res Ther 5:R285-291.
54. Elsawa SF, Novak AJ, Grote D, Konopleva M, Andreeff M, Witzig TE, and Ansell SM (2008) CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia. Leuk Res 32:1895-1902.
55. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550-562.
56. Escartin C and Brouillet E (2010) The Nrf2 pathway as a potential therapeutic target for Huntington disease A commentary on "Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington disease". Free Radic Biol Med 49:144-146.
57. Eskiocak U, Kim SB, Roig AI, Kitten E, Batten K, Cornelius C, Zou YS, Wright WE, and Shay JW (2010) CDDO-Me protects against space radiation-induced transformation of human colon epithelial cells. Radiat Res 174:27-36.
58. Ferguson HE, Kulkarni A, Lehmann GM, Garcia-Bates TM, Thatcher TH, Huxlin KR, Phipps RP, and Sime PJ (2009a) Electrophilic peroxisome proliferatoractivated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts. Am J Respir Cell Mol Biol 41:722-730.
59. Ferguson HE, Thatcher TH, Olsen KC, Garcia-Bates TM, Baglole CJ, Kottmann RM, Strong ER, Phipps RP, and Sime PJ (2009b) Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPARgamma- independent, glutathione-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 297:L912-919.
60. Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194:7-15.
61. Gao X, Deeb D, Danyluk A, Media J, Liu Y, Dulchavsky SA, and Gautam SC (2008) Immunomodulatory activity of synthetic triterpenoids: inhibition of lymphocyte proliferation, cell-mediated cytotoxicity, and cytokine gene expression through suppression of NF-kappaB. Immunopharmacol Immunotoxicol 30:581-600.
62. Gao X, Deeb D, Hao J, Liu Y, Arbab AS, Dulchavsky SA, and Gautam SC (2010) Synthetic triterpenoids inhibit growth, induce apoptosis and suppress pro-survival Akt, mTOR and NF-{kappa}B signaling proteins in colorectal cancer cells. Anticancer Res 30:785-792.
63. Gao X, Deeb D, Jiang H, Liu Y, Dulchavsky SA, and Gautam SC (2007) Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. J Neurooncol 84:147-157.
64. Gao X, Deeb D, Liu P, Liu Y, Arbab-Ali S, Dulchavsky SA, and Gautam SC (2011a) Role of reactive oxygen species (ROS) in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells. J Exp Ther Oncol 9:119-127.
65. Gao X, Liu Y, Deeb D, Arbab AS, Guo AM, Dulchavsky SA, and Gautam SC (2011b) Synthetic oleanane triterpenoid, CDDO-Me, induces apoptosis in ovarian cancer cells by inhibiting prosurvival AKT/NF-κB/mTOR signaling. Anticancer Res 31: 3673-3681.
66. Giudice A, Arra C, and Turco MC (2010) Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol Biol 647:37-74.
67. Glass CK (2006) Going nuclear in metabolic and cardiovascular disease. J Clin Invest 116:556-560.
68. Glass CK and Ogawa S (2006) Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 6:44-55.
69. Glass CK, Saijo K, Winner B, Marchetto MC, and Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918-934.
70. Goven D, Boutten A, Leçon-Malas V, Marchal-Sommé J, Amara N, Crestani B, Fournier M, Lesèche G, Soler P, Boczkowski J, et al. (2008) Altered Nrf2/Keap1- Bach1 equilibrium in pulmonary emphysema. Thorax 63:916-924.
71. Graber DJ, Park PJ, Hickey WF, and Harris BT (2011) Synthetic triterpenoid CDDO derivatives modulate cytoprotective or immunological properties in astrocytes, neurons, and microglia. J Neuroimmune Pharmacol 6:107-120.
72. Grivennikov SI, Greten FR, and Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883-899.
73. Grivennikov SI and Karin M (2010) Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21:11-19.
74. Gupta K, Patani R, Baxter P, Serio A, Story D, Tsujita T, Hayes JD, Pedersen RA, Hardingham GE, and Chandran S (2012) Human embryonic stem cell derived astrocytes mediate non-cell-autonomous neuroprotection through endogenous and drug-induced mechanisms. Cell Death Differ 19:779-787.
75. Gutierrez C and Schiff R (2011) HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 135:55-62.
76. Hail N, Jr., Konopleva M, Sporn M, Lotan R, and Andreeff M (2004) Evidence supporting a role for calcium in apoptosis induction by the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO). J Biol Chem 279:11179-1187.
77. Han SS, Peng L, Chung ST, DuBois W, Maeng SH, Shaffer AL, Sporn MB, and Janz S (2006) CDDO-Imidazolide inhibits growth and survival of c-Myc-induced mouse B cell and plasma cell neoplasms. Mol Cancer 5:22.
78. Haridas V, Hanausek M, Nishimura G, Soehnge H, Gaikwad A, Narog M, Spears E, Zoltaszek R, Walaszek Z, and Gutterman JU (2004) Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery. J Clin Invest 113:65-73.
79. Haridas V, Kim SO, Nishimura G, Hausladen A, Stamler JS, and Gutterman JU (2005) Avicinylation (thioesterification): a protein modification that can regulate the response to oxidative and nitrosative stress. Proc Natl Acad Sci USA 102: 10088-10093.
80. Hasinoff BB and Patel D (2010) The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro. Toxicol Appl Pharmacol 249:132-139.
81. Hayes JD, McMahon M, Chowdhry S, and Dinkova-Kostova AT (2010) Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 13:1713-1748.
82. He G and Karin M (2011) NF-κB and STAT3-key players in liver inflammation and cancer. Cell Res 21:159-168.
83. Heiss EH, Schachner D, Werner ER, and Dirsch VM (2009) Active NF-E2-related factor (Nrf2) contributes to keep endothelial NO synthase (eNOS) in the coupled state: role of reactive oxygen species (ROS), eNOS, and heme oxygenase (HO-1) levels. J Biol Chem 284:31579-31586.
84. Hogan CM, Thatcher TH, Sapinoro RE, Gurell MN, Ferguson HE, Pollock SJ, Jones C, Phipps RP, and Sime PJ (2011) Electrophilic PPARγ ligands attenuate IL-1β and silica-induced inflammatory mediator production in human lung fibroblasts via a PPARγ-independent mechanism. PPAR Res 2011:318134.
85. Hollander MC, Blumenthal GM, and Dennis PA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11:289-301.
86. Honda T, Janosik T, Honda Y, Han J, Liby KT, Williams CR, Couch RD, Anderson AC, Sporn MB, and Gribble GW (2004) Design, synthesis, and biological evalua-tion of biotin conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid for the isolation of the protein targets. J Med Chem 47:4923-4932.
87. Honda T, Rounds BV, Bore L, Favaloro FG, Jr., Gribble GW, Suh N, Wang Y, and Sporn MB (1999) Novel synthetic oleanane triterpenoids: a series of highly active inhibitors of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett 9:3429-3434.
88. Honda T, Rounds BV, Bore L, Finlay HJ, Favaloro FG, Jr., Suh N, Wang Y, Sporn MB, and Gribble GW (2000) Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages. J Med Chem 43:4233-4246.
89. Honda T, Rounds BV, Gribble GW, Suh N, Wang Y, and Sporn MB (1998) Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett 8:2711-2714.
90. Hong DS, Kurzrock R, Supko JG, He X, Naing A, Wheler J, Lawrence D, Eder JP, Meyer CJ, Ferguson DA, et al. (2012) A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res 18:3396-3406.
91. Hong DS, Kurzrock R, Supko JG, Lawrence DP, Wheler JJ, Meyer CJ, Mier JW, Andreeff M, Shapiro GI, and Dezube BJ (2008) Phase I trial with a novel oral NF-{kappa}B/STAT3 inhibitor RTA 402 in patients with solid tumors and lymphoid malignancies. J Clin Oncol 26 (Suppl):3517.
92. Hopkins AL (2007) Network pharmacology. Nat Biotechnol 25:1110-1111.
93. Hopkins AL (2008) Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 4:682-690.
94. Hughes DT, Martel PM, Kinlaw WB, and Eisenberg BL (2008) The synthetic triterpenoid CDDO-Im inhibits fatty acid synthase expression and has antiproliferative and proapoptotic effects in human liposarcoma cells. Cancer Invest 26:118-127.
95. Hyer ML, Croxton R, Krajewska M, Krajewski S, Kress CL, Lu M, Suh N, Sporn MB, Cryns VL, Zapata JM, et al. (2005) Synthetic triterpenoids cooperate with tumor necrosis factor-related apoptosis-inducing ligand to induce apoptosis of breast cancer cells. Cancer Res 65:4799-4808.
96. Hyer ML, Shi R, Krajewska M, Meyer C, Lebedeva IV, Fisher PB, and Reed JC (2008) Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28- oic-acid and related synthetic triterpenoids in prostate cancer. Cancer Res 68: 2927-2933.
97. Iborra M, Moret I, Rausell F, Bastida G, Aguas M, Cerrillo E, Nos P, and Beltrán B (2011) Role of oxidative stress and antioxidant enzymes in Crohn's disease. Biochem Soc Trans 39:1102-1106.
98. Ichikawa T, Li J, Meyer CJ, Janicki JS, Hannink M, and Cui T (2009) Dihydro- CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes. PLoS One 4:e8391.
99. Ikeda T, Kimura F, Nakata Y, Sato K, Ogura K, Motoyoshi K, Sporn M, and Kufe D (2005) Triterpenoid CDDO-Im downregulates PML/RARalpha expression in acute promyelocytic leukemia cells. Cell Death Differ 12:523-531.
100. Ikeda T, Nakata Y, Kimura F, Sato K, Anderson K, Motoyoshi K, Sporn M, and Kufe D (2004) Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid. Mol Cancer Ther 3:39-45.
101. Ikeda T, Sporn M, Honda T, Gribble GW, and Kufe D (2003) The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance. Cancer Res 63:5551-5558.
102. Ikushima H and Miyazono K (2010) TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 10:415-424.
103. Innamorato NG, Rojo AI, García-Yagüe AJ, Yamamoto M, de Ceballos ML, and Cuadrado A (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181:680-689.
104. Inoue S, Snowden RT, Dyer MJ, and Cohen GM (2004) CDDO induces apoptosis via the intrinsic pathway in lymphoid cells. Leukemia 18:948-952.
105. Ito Y, Pandey P, Place A, Sporn MB, Gribble GW, Honda T, Kharbanda S, and Kufe D (2000) The novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism. Cell Growth Differ 11:261-267.
106. Ito Y, Pandey P, Sporn MB, Datta R, Kharbanda S, and Kufe D (2001) The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. Mol Pharmacol 59:1094-1099.
107. Itoh K, Mimura J, and Yamamoto M (2010) Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal 13:1665-1678.
108. Jacob C (2011) Redox signalling via the cellular thiolstat. Biochem Soc Trans 39: 1247-1253.
109. Jäger S, Trojan H, Kopp T, Laszczyk MN, and Scheffler A (2009) Pentacyclic triterpene distribution in various plants - rich sources for a new group of multipotent plant extracts. Molecules 14:2016-2031.
110. Janssen-Heininger YM, Mossman BT, Heintz NH, Forman HJ, Kalyanaraman B, Finkel T, Stamler JS, Rhee SG, and van der Vliet A (2008) Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radic Biol Med 45:1-17.
111. Jazwa A and Cuadrado A (2010) Targeting heme oxygenase-1 for neuroprotection and neuroinflammation in neurodegenerative diseases. Curr Drug Targets 11: 1517-1531.
112. Ji Y, Lee HJ, Goodman C, Uskokovic M, Liby K, Sporn M, and Suh N (2006) The synthetic triterpenoid CDDO-imidazolide induces monocytic differentiation by activating the Smad and ERK signaling pathways in HL60 leukemia cells. Mol Cancer Ther 5:1452-1458.
113. Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR, and Chen PC (2008) The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann NY Acad Sci 1147:61-69.
114. Jones DP (2010) Redox sensing: orthogonal control in cell cycle and apoptosis signalling. J Intern Med 268:432-448.
115. Jutooru I, Chadalapaka G, Abdelrahim M, Basha MR, Samudio I, Konopleva M, Andreeff M, and Safe S (2010) Methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol Pharmacol 78:226-236.
116. Kaidery NA, Banerjee R, Yang L, Smirnova NA, Hushpulian DM, Liby KT, Williams CR, Yamamoto M, Kensler TW, Ratan RR, et al. (2012) Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease. Antioxid Redox Signal http://dx.doi.org/10.1089/ars.2011.4491.
117. Kannaiyan R, Shanmugam MK, and Sethi G (2011) Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer. Cancer Lett 303:9-20.
118. Kansanen E, Bonacci G, Schopfer FJ, Kuosmanen SM, Tong KI, Leinonen H, Woodcock SR, Yamamoto M, Carlberg C, Ylä-Herttuala S, et al. (2011) Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J Biol Chem 286:14019-14027.
119. Karin M (2009) NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 1:a000141.
120. Kensler TW and Wakabayashi N (2010) Nrf2: friend or foe for chemoprevention? Carcinogenesis 31:90-99.
121. Kessenbrock K, Plaks V, and Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52-67.
122. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, and Kong AN (2006) Nrf2- deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 66:11580-11584.
123. Kim EH, Deng C, Sporn MB, Royce DB, Risingsong R, Williams CR, and Liby KT (2012) CDDO-methyl ester delays breast cancer development in Brca1-mutated mice. Cancer Prev Res (Phila) 5:89-97.
124. Kim EH, Deng CX, Sporn MB, and Liby KT (2011) CDDO-imidazolide induces DNA damage, G2/M arrest and apoptosis in BRCA1-mutated breast cancer cells. Cancer Prev Res (Phila) 4:425-434.
125. Kim EH and Surh YJ (2006) 15-deoxy-Delta12,14-prostaglandin J2 as a potential endogenous regulator of redox-sensitive transcription factors. Biochem Pharmacol 72:1516-1528.
126. Kim JE, You DJ, Lee C, Ahn C, Seong JY, and Hwang JI (2010) Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. Cell Signal 22:1645-1654.
127. Kim KB, Lotan R, Yue P, Sporn MB, Suh N, Gribble GW, Honda T, Wu GS, Hong WK, and Sun SY (2002) Identification of a novel synthetic triterpenoid, methyl-2- cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells. Mol Cancer Ther 1:177-184.
128. Klaassen CD and Reisman SA (2010) Nrf2 the rescue: effects of the antioxidative/ electrophilic response on the liver. Toxicol Appl Pharmacol 244:57-65.
129. Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, Eguchi M, Wada Y, Kumagai Y, and Yamamoto M (2009) The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol 29:493-502.
130. Koenitzer JR and Freeman BA (2010) Redox signaling in inflammation: interactions of endogenous electrophiles and mitochondria in cardiovascular disease. Ann NY Acad Sci 1203:45-52.
131. Konopleva M, Contractor R, Kurinna SM, Chen W, Andreeff M, and Ruvolo PP (2005) The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells. Leukemia 19:1350-1354.
132. Konopleva M, Tsao T, Estrov Z, Lee RM, Wang RY, Jackson CE, McQueen T, Monaco G, Munsell M, Belmont J, et al. (2004) The synthetic triterpenoid 2-cyano-3,12- dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia. Cancer Res 64:7927-7935.
133. Konopleva M, Tsao T, Ruvolo P, Stiouf I, Estrov Z, Leysath CE, Zhao S, Harris D, Chang S, Jackson CE, et al. (2002) Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood 99:326-335.
134. Konopleva M, Zhang W, Shi YX, McQueen T, Tsao T, Abdelrahim M, Munsell MF, Johansen M, Yu D, Madden T, et al. (2006) Synthetic triterpenoid 2-cyano-3,12- dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells. Mol Cancer Ther 5:317-328.
135. Koschmieder S, D'Alò F, Radomska H, Schöneich C, Chang JS, Konopleva M, Kobayashi S, Levantini E, Suh N, Di Ruscio A, et al. (2007) CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational upregulation of p42 CCAAT enhancer binding protein alpha. Blood 110:3695-3705.
136. Kress CL, Konopleva M, Martínez-García V, Krajewska M, Lefebvre S, Hyer ML, McQueen T, Andreeff M, Reed JC, and Zapata JM (2007) Triterpenoids display single agent anti-tumor activity in a transgenic mouse model of chronic lymphocytic leukemia and small B cell lymphoma. PLoS One 2:e559.
137. Kulkarni AA, Thatcher TH, Olsen KC, Maggirwar SB, Phipps RP, and Sime PJ (2011) PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis. PLoS One 6:e15909.
138. Kuriyan AE, Lehmann GM, Kulkarni AA, Woeller CF, Feldon SE, Hindman HB, Sime PJ, Huxlin KR, and Phipps RP (2012) Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: A potentially novel therapy for corneal scarring. Exp Eye Res 94:136-145.
139. Lapillonne H, Konopleva M, Tsao T, Gold D, McQueen T, Sutherland RL, Madden T, and Andreeff M (2003) Activation of peroxisome proliferator-activated receptor gamma by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells. Cancer Res 63: 5926-5939.
140. Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, Shen J, Chen CT, Huo L, Hsu MC, et al. (2009) KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell 36:131-140.
141. Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, and Johnson JA (2005) Nrf2, a multi-organ protector? Faseb J 19:1061-1066.
142. Leonard MO, Kieran NE, Howell K, Burne MJ, Varadarajan R, Dhakshinamoorthy S, Porter AG, O'Farrelly C, Rabb H, and Taylor CT (2006) Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury. Faseb J 20:2624-2626.
143. Levy ED, Landry CR, and Michnick SW (2010) Cell signaling. Signaling through cooperation. Science 328:983-984.
144. Li J, Ichikawa T, Janicki JS, and Cui T (2009) Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets 13:785-794.
145. Li M, Sun K, Redelman D, Welniak LA, and Murphy WJ (2010) The triterpenoid CDDO-Me delays murine acute graft-versus-host disease with the preservation of graft-versus-tumor effects after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 16:739-750.
146. Li N, Grivennikov SI, and Karin M (2011) The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 19:429-431.
147. Liao D, Liu Z, Wrasidlo WJ, Luo Y, Nguyen G, Chen T, Xiang R, and Reisfeld RA (2011) Targeted therapeutic remodeling of the tumor microenvironment improves an HER-2 DNA vaccine and prevents recurrence in a murine breast cancer model. Cancer Res 71:5688-5696.
148. Liby K, Black CC, Royce DB, Williams CR, Risingsong R, Yore MM, Liu X, Honda T, Gribble GW, Lamph WW, et al. (2008a) The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis. Mol Cancer Ther 7:1251-1257.
149. Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, et al. (2005) The synthetic triterpenoids, CDDO and CDDOimidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 65:4789-4798.
150. Liby K, Risingsong R, Royce DB, Williams CR, Ma T, Yore MM, and Sporn MB (2009) Triterpenoids CDDO-methyl ester or CDDO-ethyl amide and rexinoids LG100268 or NRX194204 for prevention and treatment of lung cancer in mice. Cancer Prev Res (Phila) 2:1050-1058.
151. Liby K, Risingsong R, Royce DB, Williams CR, Yore MM, Honda T, Gribble GW, Lamph WW, Vannini N, Sogno I, et al. (2008b) Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268. Clin Cancer Res 14:4556-4563.
152. Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, Honda T, Gribble GW, Dmitrovsky E, Sporn TA, and Sporn MB (2007a) The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res 67:2414-2419.
153. Liby K, Voong N, Williams CR, Risingsong R, Royce DB, Honda T, Gribble GW, Sporn MB, and Letterio JJ (2006) The synthetic triterpenoid CDDO-Imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells. Clin Cancer Res 12:4288-4293.
154. Liby KT, Royce DB, Risingsong R, Williams CR, Maitra A, Hruban RH, and Sporn MB (2010) Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. Cancer Prev Res (Phila) 3:1427-1434.
155. Liby KT, Yore MM, and Sporn MB (2007b) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7:357-369.
156. Ling X, Konopleva M, Zeng Z, Ruvolo V, Stephens LC, Schober W, McQueen T, Dietrich M, Madden TL, and Andreeff M (2007) The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling. Cancer Res 67:4210-4218.
157. Liu M, Grigoryev DN, Crow MT, Haas M, Yamamoto M, Reddy SP, and Rabb H (2009) Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int 76:277-285.
158. Liu Y, Gao X, Deeb D, and Gautam SC (2012) Oleanane triterpenoid CDDO-Me inhibits Akt activity without affecting PDK1 kinase or PP2A phosphatase activity in cancer cells. Biochem Biophys Res Commun 417:570-575.
159. Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, and Gabrilovich D (2011) Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest 121:4015-4029.
160. Maicas N, Ferrándiz ML, Brines R, Ibáñez L, Cuadrado A, Koenders MI, van den Berg WB, and Alcaraz MJ (2011) Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal 15:889-901.
161. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, et al. (2008) Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 178:592-604.
162. Mancuso C and Barone E (2009) The heme oxygenase/biliverdin reductase pathway in drug research and development. Curr Drug Metab 10:579-594.
163. Mantovani A, Allavena P, Sica A, and Balkwill F (2008) Cancer-related inflammation. Nature 454:436-444.
164. Marnett LJ, Riggins JN, and West JD (2003) Endogenous generation of reactive oxidants and electrophiles and their reactions with DNA and protein. J Clin Invest 111:583-593.
165. McNamara CR and Degterev A (2011) Small-molecule inhibitors of the PI3K signaling network. Future Med Chem 3:549-565.
166. Melichar B, Konopleva M, Hu W, Melicharova K, Andreeff M, and Freedman RS (2004) Growth-inhibitory effect of a novel synthetic triterpenoid, 2-cyano-3,12- dioxoolean-1,9-dien-28-oic acid, on ovarian carcinoma cell lines not dependent on peroxisome proliferator-activated receptor-gamma expression. Gynecol Oncol 93: 149-154.
167. Meyer C, Yore M, Ferguson D, Watkins B, Fey E, Sporn M, Huff J, and Sonis S (2006) RTA 402 suppresses tumor and treatment induced inflammation, sensitizing tumors to and protecting normal tissue from radiation (Abstract). Eur J Cancer Suppl 4:162.
168. Minns LA, Buzoni-Gatel D, Ely KH, Rachinel N, Luangsay S, and Kasper LH (2004) A novel triterpenoid induces transforming growth factor beta production by intraepithelial lymphocytes to prevent ileitis. Gastroenterology 127:119-126.
169. Mix KS, Coon CI, Rosen ED, Suh N, Sporn MB, and Brinckerhoff CE (2004) Peroxisome proliferator-activated receptor-gamma-independent repression of collagenase gene expression by 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and prostaglandin 15-deoxy-delta(12,14) J2: a role for Smad signaling. Mol Pharmacol 65: 309-318.
170. Mix KS, Mengshol JA, Benbow U, Vincenti MP, Sporn MB, and Brinckerhoff CE (2001) A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines. Arthritis Rheum 44:1096-1104.
171. Montero AJ and Jassem J (2011) Cellular redox pathways as a therapeutic target in the treatment of cancer. Drugs 71:1385-1396.
172. Na HK and Surh YJ (2006) Transcriptional regulation via cysteine thiol modification: a novel molecular strategy for chemoprevention and cytoprotection. Mol Carcinog 45:368-380.
173. Nagai N, Thimmulappa RK, Cano M, Fujihara M, Izumi-Nagai K, Kong X, Sporn MB, Kensler TW, Biswal S, and Handa JT (2009) Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic Biol Med 47:300-306.
174. Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, et al. (2010) Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 16:1812-1823.
175. Nathan C and Ding A (2010) Nonresolving inflammation. Cell 140:871-882.
176. Negi G, Kumar A, Joshi RP, and Sharma SS (2011) Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: old perspective with a new angle. Biochem Biophys Res Commun 408:1-5.
177. Neurath MF and Finotto S (2011) IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 22: 83-89.
178. Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, Liby KT, Risingsong R, Sporn M, Beal MF, et al. (2011) Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med 51:88-96.
179. Nichols DP, Ziady AG, Shank SL, Eastman JF, and Davis PB (2009) The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease. Am J Physiol Lung Cell Mol Physiol 297:L828-836.
180. Olsen AM, Eisenberg BL, Kuemmerle NB, Flanagan AJ, Morganelli PM, Lombardo PS, Swinnen JV, and Kinlaw WB (2010) Fatty acid synthesis is a therapeutic target in human liposarcoma. Int J Oncol 36:1309-1314.
181. Osburn WO, Yates MS, Dolan PD, Chen S, Liby KT, Sporn MB, Taguchi K, Yamamoto M, and Kensler TW (2008) Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci 104: 218-227.
182. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 59:1593-1600.
183. Pareek TK, Belkadi A, Kesavapany S, Zaremba A, Loh SL, Bai L, Cohen ML, Meyer C, Liby KT, Miller RH, et al. (2011) Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci Rep 1:201.
184. Paulsen CE and Carroll KS (2010) Orchestrating redox signaling networks through regulatory cysteine switches. ACS Chem Biol 5:47-62.
185. Pedersen IM, Kitada S, Schimmer A, Kim Y, Zapata JM, Charboneau L, Rassenti L, Andreeff M, Bennett F, Sporn MB, et al. (2002) The triterpenoid CDDO induces apoptosis in refractory CLL B cells. Blood 100:2965-2972.
186. Pergola PE, Krauth M, Huff JW, Ferguson DA, Ruiz S, Meyer CJ, and Warnock DG (2011a) Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am J Nephrol 33:469-476.
187. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, et al. (2011b) Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 365:327-336.
188. Petronelli A, Pannitteri G, and Testa U (2009a) Triterpenoids as new promising anticancer drugs. Anticancer Drugs 20:880-892.
189. Petronelli A, Pelosi E, Santoro S, Saulle E, Cerio AM, Mariani G, Labbaye C, and Testa U (2011) CDDO-Im is a stimulator of megakaryocytic differentiation. Leuk Res 35:534-544.
190. Petronelli A, Saulle E, Pasquini L, Petrucci E, Mariani G, Biffoni M, Ferretti G, Scambia G, Benedetti-Panici P, Greggi S, et al. (2009b) High sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide. Cancer Lett 282:214-228.
191. Phillips DR, Rasbery JM, Bartel B, and Matsuda SP (2006) Biosynthetic diversity in plant triterpene cyclization. Curr Opin Plant Biol 9:305-314.
192. Pitha-Rowe I, Liby K, Royce D, and Sporn M (2009) Synthetic triterpenoids attenuate cytotoxic retinal injury: cross-talk between Nrf2 and PI3K/AKT signaling through inhibition of the lipid phosphatase PTEN. Invest Ophthalmol Vis Sci 50:5339-5347.
193. Place AE, Suh N, Williams CR, Risingsong R, Honda T, Honda Y, Gribble GW, Leesnitzer LM, Stimmel JB, Willson TM, et al. (2003) The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clin Cancer Res 9:2798-2806.
194. Qian BZ and Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39-51.
195. Rakoff-Nahoum S and Medzhitov R (2009) Toll-like receptors and cancer. Nat Rev Cancer 9:57-63.
196. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, and Biswal S (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest 114:1248-1259.
197. Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, et al. (2005) Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med 202:47-59.
198. Raval CM and Lee PJ (2010) Heme oxygenase-1 in lung disease. Curr Drug Targets 11:1532-1540.
199. Ray DM, Morse KM, Hilchey SP, Garcia TM, Felgar RE, Maggirwar SB, Phipps RP, and Bernstein SH (2006) The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor gammaindependent pathway. Exp Hematol 34:1202-1211.
200. Reddy NM, Kleeberger SR, Kensler TW, Yamamoto M, Hassoun PM, and Reddy SP (2009a) Disruption of Nrf2 impairs the resolution of hyperoxia-induced acute lung injury and inflammation in mice. J Immunol 182:7264-7271.
201. Reddy NM, Suryanaraya V, Yates MS, Kleeberger SR, Hassoun PM, Yamamoto M, Liby KT, Sporn MB, Kensler TW, and Reddy SP (2009b) The triterpenoid CDDOimidazolide confers potent protection against hyperoxic acute lung injury in mice. Am J Respir Crit Care Med 180:867-874.
202. Reisman SA, Buckley DB, Tanaka Y, and Klaassen CD (2009) CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes. Toxicol Appl Pharmacol 236:109-114.
203. Riccioni R, Senese M, Diverio D, Riti V, Mariani G, Boe A, LoCoco F, Foà R, Peschle C, Sporn M, et al. (2008) Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels. Leuk Res 32:1244-1258.
204. Rigoulet M, Yoboue ED, and Devin A (2011) Mitochondrial ROS generation and its regulation: mechanisms involved in H(2)O(2) signaling. Antioxid Redox Signal 14:459-468.
205. Ross R (1999) Atherosclerosis-an inflammatory disease. N Engl J Med 340:115-126.
206. Ruffell B, DeNardo DG, Affara NI, and Coussens LM (2010) Lymphocytes in cancer development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev 21:3-10.
207. Ryu K, Choy E, Yang C, Susa M, Hornicek FJ, Mankin H, and Duan Z (2010a) Activation of signal transducer and activator of transcription 3 (Stat3) pathway in osteosarcoma cells and overexpression of phosphorylated-Stat3 correlates with poor prognosis. J Orthop Res 28:971-978.
208. Ryu K, Susa M, Choy E, Yang C, Hornicek FJ, Mankin HJ, and Duan Z (2010b) Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway. BMC Cancer 10:187.
209. Saha PK, Reddy VT, Konopleva M, Andreeff M, and Chan L (2010) The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent antidiabetic effects in diet-induced diabetic mice and Lepr(db/db) mice. J Biol Chem 285:40581-40592.
210. Samudio I, Konopleva M, Hail N, Jr., Shi YX, McQueen T, Hsu T, Evans R, Honda T, Gribble GW, Sporn M, Gilbert HF, Safe S, and Andreeff M (2005) 2-Cyano-3,12- dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) directly targets mitochondrial glutathione to induce apoptosis in pancreatic cancer. J Biol Chem 280:36273-36282.
211. Samudio I, Konopleva M, Pelicano H, Huang P, Frolova O, Bornmann W, Ying Y, Evans R, Contractor R, and Andreeff M (2006) A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate: direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis. Mol Pharmacol 69:1182-1193.
212. Samudio I, Kurinna S, Ruvolo P, Korchin B, Kantarjian H, Beran M, Dunner K, Jr., Kondo S, Andreeff M, and Konopleva M (2008) Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells. Mol Cancer Ther 7:1130-1139.
213. Santibañez JF, Quintanilla M, and Bernabeu C (2011) TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci 121:233-251.
214. Sardina JL, López-Ruano G, Sánchez-Sánchez B, and Hernández-Hernández A (2011) CDDO-Im, an antitumor molecule that also improves platetet production. Leuk Res 35:427-428.
215. Schmidt MV, Brüne B, and von Knethen A (2010) The nuclear hormone receptor PPARγ as a therapeutic target in major diseases. ScientificWorldJournal 10:2181-2197.
216. Schroder K and Tschopp J (2010) The inflammasomes. Cell 140:821-832.
217. Schroder K, Zhou R, and Tschopp J (2010) The NLRP3 inflammasome: a sensor for metabolic danger? Science 327:296-300.
218. Segal BH, Han W, Bushey JJ, Joo M, Bhatti Z, Feminella J, Dennis CG, Vethanayagam RR, Yull FE, Capitano M, et al. (2010) NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One 5:e9631.
219. Sheng H and Sun H (2011) Synthesis, biology and clinical significance of pentacyclic triterpenes: a multi-target approach to prevention and treatment of metabolic and vascular diseases. Nat Prod Rep 28:543-593.
220. Shiao SL, Ganesan AP, Rugo HS, and Coussens LM (2011) Immune microenvironments in solid tumors: new targets for therapy. Genes Dev 25:2559-2572.
221. Shibata T, Saito S, Kokubu A, Suzuki T, Yamamoto M, and Hirohashi S (2010) Global downstream pathway analysis reveals a dependence of oncogenic NF-E2- related factor 2 mutation on the mTOR growth signaling pathway. Cancer Res 70:9095-9105.
222. Shin S, Wakabayashi J, Yates MS, Wakabayashi N, Dolan PM, Aja S, Liby KT, Sporn MB, Yamamoto M, and Kensler TW (2009) Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol 620:138-144.
223. Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, Yamamoto M, and Kensler TW (2007) NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol 27:7188-7197.
224. Shiraki T, Kamiya N, Shiki S, Kodama TS, Kakizuka A, and Jingami H (2005) Alpha,beta-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor gamma. J Biol Chem 280: 14145-14153.
225. Shishodia S, Sethi G, Konopleva M, Andreeff M, and Aggarwal BB (2006) A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin Cancer Res 12:1828-1838.
226. Shuttleworth SJ, Silva FA, Cecil AR, Tomassi CD, Hill TJ, Raynaud FI, Clarke PA, and Workman P (2011) Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors. Curr Med Chem 18:2686-2714.
227. Siedenburg G and Jendrossek D (2011) Squalene-hopene cyclases. Appl Environ Microbiol 77:3905-3915.
228. Singh J, Petter RC, Baillie TA, and Whitty A (2011) The resurgence of covalent drugs. Nat Rev Drug Discov 10:307-317.
229. Slocum SL and Kensler TW (2011) Nrf2: control of sensitivity to carcinogens. Arch Toxicol 85:273-284.
230. Speranza G, Gutierrez ME, Kummar S, Strong JM, Parker RJ, Collins J, Yu Y, Cao L, Murgo AJ, Doroshow JH, et al. (2012) Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors. Cancer Chemother Pharmacol 69:431-438.
231. Sporn MB and Liby KT (2012) NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer 12:564-571.
232. Sporn MB, Liby K, Yore MM, Suh N, Albini A, Honda T, Sundararajan C, and Gribble GW (2007) Platforms and networks in triterpenoid pharmacology. Drug Dev Res 68:174-182.
233. Sporn MB, Liby KT, Yore MM, Fu L, Lopchuk JM, and Gribble GW (2011) New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 74:537-545.
234. Stack C, Ho D, Wille E, Calingasan NY, Williams C, Liby K, Sporn M, Dumont M, and Beal MF (2010) Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease. Free Radic Biol Med 49:147-158.
235. Stadheim TA, Suh N, Ganju N, Sporn MB, and Eastman A (2002) The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) potently enhances apoptosis induced by tumor necrosis factor in human leukemia cells. J Biol Chem 277:16448-16455.
236. Strober W and Fuss IJ (2011) Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140:1756-1767.
237. Sugawara A, Uruno A, Kudo M, Matsuda K, Yang CW, and Ito S (2010) Effects of PPAR_ on hypertension, atherosclerosis, and chronic kidney disease. Endocr J 57:847-852.
238. Suh N, Paul S, Lee HJ, Yoon T, Shah N, Son AI, Reddi AH, Medici D, and Sporn MB (2012) Synthetic triterpenoids, CDDO-Imidazolide and CDDO-Ethyl amide, induce chondrogenesis. Osteoarthritis Cartilage 20:446-450.
239. Suh N, Roberts AB, Birkey Reffey S, Miyazono K, Itoh S, ten Dijke P, Heiss EH, Place AE, Risingsong R, Williams CR, et al. (2003a) Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling. Cancer Res 63:1371-1376.
240. Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF, Maue RA, Place AE, Porter DM, Spinella MJ, et al. (1999) A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res 59:336-341.
241. Suh WS, Kim YS, Schimmer AD, Kitada S, Minden M, Andreeff M, Suh N, Sporn M, and Reed JC (2003b) Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL. Leukemia 17:2122-2129.
242. Sun K, Li M, Konopleva M, Konoplev S, Stephens LC, Kornblau SM, Frolova O, Wilkins DE, Ma W, Welniak LA, et al. (2007) The synthetic triterpenoid, CDDO, suppresses alloreactive T cell responses and reduces murine early acute graftversus- host disease mortality. Biol Blood Marrow Transplant 13:521-529.
243. 12,14-prostaglandin J2, an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling Biochem Pharmacol 82:1335-1351.
244. Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, et al. (2009) Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci USA 106:250-255.
245. Suzuki M, Betsuyaku T, Nagai K, Fuke S, Nasuhara Y, Kaga K, Kondo S, Hamamura I, Hata J, Takahashi H, et al. (2008) Decreased airway expression of vascular endothelial growth factor in cigarette smoke-induced emphysema in mice and COPD patients. Inhal Toxicol 20:349-359.
246. Tabe Y, Konopleva M, Kondo Y, Contractor R, Tsao T, Konoplev S, Shi Y, Ling X, Watt JC, Tsutsumi-Ishii Y, et al. (2007) PPARgamma-active triterpenoid CDDO enhances ATRA-induced differentiation in APL. Cancer Biol Ther 6:1967-1977.
247. Taguchi K, Motohashi H, and Yamamoto M (2011) Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16:123-140.
248. Tanaka Y, Aleksunes LM, Goedken MJ, Chen C, Reisman SA, Manautou JE, and Klaassen CD (2008) Coordinated induction of Nrf2 target genes protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity. Toxicol Appl Pharmacol 231:364-373.
249. Tanaka Y, Maher JM, Chen C, and Klaassen CD (2007) Hepatic ischemiareperfusion induces renal heme oxygenase-1 via NF-E2-related factor 2 in rats and mice. Mol Pharmacol 71:817-825.
250. Tang W and Eisenbrand G (1992) Chinese Drugs of Plant Origin, Springer-Verlag, Berlin.
251. Theiss AL, Vijay-Kumar M, Obertone TS, Jones DP, Hansen JM, Gewirtz AT, Merlin D, and Sitaraman SV (2009) Prohibitin is a novel regulator of antioxidant response that attenuates colonic inflammation in mice. Gastroenterology 137:199-208.
252. Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Traore K, Bream JH, Trush MA, Liby KT, Sporn MB, Kensler TW, et al. (2007) Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 9:1963-1970.
253. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, and Biswal S (2006a) Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 116:984-995.
254. Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, Sporn MB, Yamamoto M, Kensler TW, and Biswal S (2006b) Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun 351:883-889.
255. Thu KL, Pikor LA, Chari R, Wilson IM, Macaulay CE, English JC, Tsao MS, Gazdar AF, Lam S, Lam WL, et al. (2011) Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer. J Thorac Oncol 6:1521-1529.
256. To C, Kulkarni S, Pawson T, Honda T, Gribble GW, Sporn MB, Wrana JL, and Di Guglielmo GM (2008) The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9- dien-28-oic acid-imidazolide alters transforming growth factor beta-dependent signaling and cell migration by affecting the cytoskeleton and the polarity complex. J Biol Chem 283:11700-11713.
257. To C, Shilton BH, and Di Guglielmo GM (2010) Synthetic triterpenoids target the Arp2/3 complex and inhibit branched actin polymerization. J Biol Chem 285: 27944-27957.
258. Townson JL, Macdonald IC, Liby KT, Mackenzie L, Dales DW, Hedley BD, Foster PJ, Sporn MB, and Chambers AF (2011) The synthetic triterpenoid CDDOImidazolide suppresses experimental liver metastasis. Clin Exp Metastasis 28: 309-317.
259. Trachootham D, Alexandre J, and Huang P (2009) Targeting cancer cells by ROSmediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579-591.
260. Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao PJ, Achanta G, Arlinghaus RB, Liu J, et al. (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10:241-252.
261. Tran K, Risingsong R, Royce D, Williams CR, Sporn MB, and Liby K (2012) The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice. Cancer Prev Res (Phila) 5:726-734.
262. Tran TA, McCoy MK, Sporn MB, and Tansey MG (2008) The synthetic triterpenoid CDDO-methyl ester modulates microglial activities, inhibits TNF production, and provides dopaminergic neuroprotection. J Neuroinflammation 5:14.
263. Tsao T, Kornblau S, Safe S, Watt JC, Ruvolo V, Chen W, Qiu Y, Coombes KR, Ju Z, Abdelrahim M, et al. (2010) Role of peroxisome proliferator-activated receptorgamma and its coactivator DRIP205 in cellular responses to CDDO (RTA-401) in acute myelogenous leukemia. Cancer Res 70:4949-4960.
264. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, and Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11:329-341.
265. Vannini N, Lorusso G, Cammarota R, Barberis M, Noonan DM, Sporn MB, and Albini A (2007) The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol Cancer Ther 6:3139-3146.
266. Vazquez-Torres A (2012) Redox active thiol sensors of oxidative and nitrosative stress. Antioxid Redox Signal http://dx.doi.org/10.1089/ars.2012.4522.
267. Vázquez N, Greenwell-Wild T, Marinos NJ, Swaim WD, Nares S, Ott DE, Schubert U, Henklein P, Orenstein JM, Sporn MB, et al. (2005) Human immunodeficiency virus type 1-induced macrophage gene expression includes the p21 gene, a target for viral regulation. J Virol 79:4479-4491.
268. Venè R, Larghero P, Arena G, Sporn MB, Albini A, and Tosetti F (2008) Glycogen synthase kinase 3beta regulates cell death induced by synthetic triterpenoids. Cancer Res 68:6987-6996.
269. Vidal M, Cusick ME, and Barabási AL (2011) Interactome networks and human disease. Cell 144:986-998.
270. Virchow R (1867) Die Krankhaften Geschwulste, Berlin, August Hirschwald.
271. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, and Kensler TW (2010) When NRF2 talks, who's listening? Antioxid Redox Signal 13:1649-1663.
272. Wander SA, Hennessy BT, and Slingerland JM (2011) Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest 121:1231-1241.
273. Wang JS, Shen X, He X, Zhu YR, Zhang BC, Wang JB, Qian GS, Kuang SY, Zarba A, Egner PA, et al. (1999) Protective alterations in phase 1 and 2 metabolism of aflatoxin B1 by oltipraz in residents of Qidong, People's Republic of China. J Natl Cancer Inst 91:347-354.
274. Wang Y, Porter WW, Suh N, Honda T, Gribble GW, Leesnitzer LM, Plunket KD, Mangelsdorf DJ, Blanchard SG, Willson TM, et al. (2000) A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma. Mol Endocrinol 14:1550-1556.
275. Wei Y, Gong J, Yoshida T, Eberhart CG, Xu Z, Kombairaju P, Sporn MB, Handa JT, and Duh EJ (2011) Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury. Free Radic Biol Med 51:216-224.
276. Weis SM and Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359-1370.
277. Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, et al. (2011) Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 70:844-850.
278. Wu ML, Ho YC, and Yet SF (2011a) A central role of heme oxygenase-1 in cardiovascular protection. Antioxid Redox Signal 15:1835-1846.
279. Wu QQ, Wang Y, Senitko M, Meyer C, Wigley WC, Ferguson DA, Grossman E, Chen J, Zhou XJ, Hartono J, et al. (2011b) Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1. Am J Physiol Renal Physiol 300:F1180-1192.
280. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, and Yamamoto M (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 28:2758-2770.
281. Yang C, Hornicek FJ, Wood KB, Schwab JH, Choy E, Mankin H, and Duan Z (2010) Blockage of Stat3 with CDDO-Me inhibits tumor cell growth in chordoma. Spine (Phila Pa 1976) 35:1668-1675.
282. Yang L, Calingasan NY, Thomas B, Chaturvedi RK, Kiaei M, Wille EJ, Liby KT, Williams C, Royce D, Risingsong R, et al. (2009) Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLoS One 4:e5757.
283. Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddigari S, Sutter TR, Baumgartner KJ, Roebuck BD, Liby KT, Yore MM, et al. (2006) Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28- oyl]imidazole. Cancer Res 66:2488-2494.
284. Yates MS, Tauchi M, Katsuoka F, Flanders KC, Liby KT, Honda T, Gribble GW, Johnson DA, Johnson JA, Burton NC, et al. (2007) Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2- regulated genes. Mol Cancer Ther 6:154-162.
285. Yates MS, Tran QT, Dolan PM, Osburn WO, Shin S, McCulloch CC, Silkworth JB, Taguchi K, Yamamoto M, Williams CR, et al. (2009) Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30:1024-1031.
286. Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, and Takahashi S (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 60:1343-1353.
287. Yore MM, Kettenbach AN, Sporn MB, Gerber SA, and Liby KT (2011) Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR. PLoS One 6:e22862.
288. Yore MM, Liby KT, Honda T, Gribble GW, and Sporn MB (2006) The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-kappaB activation through direct inhibition of IkappaB kinase beta. Mol Cancer Ther 5:3232-3239.
289. Youn JI and Gabrilovich DI (2010) The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 40:2969-2975.
290. Yu H, Pardoll D, and Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798-809.
291. Yu M, Li H, Liu Q, Liu F, Tang L, Li C, Yuan Y, Zhan Y, Xu W, Li W, et al. (2011) Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal 23:883-892.
292. Yue P, Zhou Z, Khuri FR, and Sun SY (2006) Depletion of intracellular glutathione contributes to JNK-mediated death receptor 5 upregulation and apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me). Cancer Biol Ther 5:492-497.
293. Zhang C, Ni X, Konopleva M, Andreeff M, and Duvic M (2004) The novel synthetic oleanane triterpenoid CDDO (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) induces apoptosis in Mycosis fungoides/Sézary syndrome cells. J Invest Dermatol 123:380-387.
294. Zhang F, Wang S, Zhang M, Weng Z, Li P, Gan Y, Zhang L, Cao G, Gao Y, Leak RK, et al. (2012) Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury. Stroke 43:1390-1397.
295. Zhao L, Lee JY, and Hwang DH (2011) Inhibition of pattern recognition receptormediated inflammation by bioactive phytochemicals. Nutr Rev 69:310-320.
296. Zoncu R, Efeyan A, and Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21-35.
297. Zou W, Chen S, Liu X, Yue P, Sporn MB, Khuri FR, and Sun SY (2007) c-FLIP downregulation contributes to apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) in human lung cancer cells. Cancer Biol Ther 6:1614-1620.
298. Zou W, Liu X, Yue P, Zhou Z, Sporn MB, Lotan R, Khuri FR, and Sun SY (2004) c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12- dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res 64:7570-7578.
299. Zou W, Yue P, Khuri FR, and Sun SY (2008) Coupling of endoplasmic reticulum stress to CDDO-Me-induced up-regulation of death receptor 5 via a CHOPdependent mechanism involving JNK activation. Cancer Res 68:7484-7492.