Semisynthetic pentacyclic triterpenoids in the cancer setting: Oleanolic acid and its derivatives

Pentacyclic Triterpenes as Promising Agents in Cancer

Volumn , Issue , 2011, Pages 191-248

  Salvador, Jorge A R ^a,b   Leal, Ana S M ^a   Santos, Rita C ^a  

^a UNIVERSITY OF COIMBRA   (Portugal)

^b INSTITUTO PEDRO NUNES   (Portugal)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84891967174     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter

References (216)

1. Liby, KT; Yore, MM; Sporn, MB. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat. Rev. Cancer, 2007 7, (5), 357-369.
2. Ovesna, Z; Vachalkova, A; Horvathova, K; Tothova, D. Pentacyclic triterpenoic acids: new chemoprotective compounds. Neoplasma, 2004 51, (5), 327-333.
3. Liu, J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol., 1995 49, (2), 57-68.
4. Novotny, L; Vachalkova, A; Biggs, D. Ursolic acid: An anti-tumorigenic and chemopreventive activity. Neoplasma, 2001 48, (4), 241-246.
5. Fontanay, S; Grare, M; Mayer, J; Finance, C; Duval, RE. Ursolic, oleanolic and betulinic acids: Antibacterial spectra and selectivity indexes. J. Ethnopharmacol., 2008 120, (2), 272-276.
6. Horiuchi, K; Shiota, S; Hatano, T; Yoshida, T; Kuroda, T; Tsuchiya, T. Antimicrobial activity of oleanolic acid from Salvia officinalis and related compounds on vancomycin-resistant enterococci (VRIE). Biol. Pharm. Bull., 2007 30, (6), 1147-1149.
7. Hichri, F; Ben Jannet, H; Cheriaa, J; Jegham, S; Mighri, Z. Antibacterial activities of a few prepared derivatives of oleanolic acid and of other natural triterpenic compounds. Compt. Rendus Chem., 2003 6, (4), 473-483.
8. Tanachatchairatana, T; Bremner, JB; Chokchaisiri, R; Suksamrarn, A. Antimycobacterial activity of cinnamate-based esters of the triterpenes betulinic, oleanolic and ursolic acids. Chem. Pharm. Bull., 2008 56, (2), 194-198.
9. Gu, JQ; Wang, YH; Franzblau, SG; Montenegro, G; Timmermann, BN. Constituents of Quinchamalium majus with potential antitubercular activity. Z. Naturforsch. C, 2004 59, (11-12), 797-802.
10. Rivero-Cruz, JF; Zhu, M; Kinghorn, AD; Wu, CD. Antimicrobial constituents of Thompson seedless raisins (Vitis vinifera) against selected oral pathogens. Phytochemistry Lett., 2008 1, (3), 151-154.
11. Torres-Santos, EC; Lopes, D; Oliveira, RR; Carauta, JPP; Falcao, CAB; Kaplan, AAC; Rossi-Bergmann, B. Antileishmanial activity of isolated triterpenoids from Pourouma guianensis. Phytomedicine, 2004 11, (2-3), 114-120.
12. Gnoatto, SCB; Dalla Vechia, L; Lencina, CL; Dassonville-Klimpt, A; Da Nascimento, S; Mossalayi, D; Guillon, J; Gosmann, G; Sonnet, P. Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents. J. Enzym. Inhib. Med. Chem., 2008 23, (5), 604-610.
13. Zhang, Y; Li, JX; Zhao, JW; Wang, SZ; Pan, Y; Tanaka, K; Kadota, S. Synthesis and activity of oleanolic acid derivatives, a novel class of inhibitors of osteoclast formation. Bioorg. Med. Chem. Lett., 2005 15, (6), 1629-1632.
14. Rajasekaran, M; Bapna, JS; Lakshmanan, S; Nair, AGR; Veliath, AJ; Panchanadam, M. Antifertility Effect in Male-Rats of Oleanolic Acid, a Triterpene from Eugenia-Jambolana Flowers. J. Ethnopharmacol., 1988 24, (1), 115-121.
15. Somova, LO; Nadar, A; Rammanan, P; Shode, FO. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine, 2003 10, (2-3), 115-121.
16. Somova, LI; Shode, FO; Mipando, M. Cardiotonic and antidysrhythmic effects of oleanolic and ursolic acids, methyl maslinate and uvaol. Phytomedicine, 2004 11, (2-3), 121-129.
17. Alvarez, ME; Maria, AOM; Saad, JR. Diuretic activity of Fabiana patagonica in rats. Phytother. Res., 2002 16, (1), 71-73.
18. Wen, XA; Sun, HB; Liu, J; Cheng, KG; Zhang, P; Zhang, LY; Hao, J; Zhang, LY; Ni, PZ; Zographos, SE; Leonidas, DD; Alexacou, KM; Gimisis, T; Hayes, JM; Oikonomakos, NG. Naturally occurring pentacyclic triterpenes as inhibitors of glycogen phosphorylase: Synthesis, structure-activity relationships, and X-ray crystallographic studies. J. Med. Chem., 2008 51, (12), 3540-3554.
19. Chen, J; Liu, J; Zhang, LY; Wu, GZ; Hua, WY; Wu, XM; Sun, HB. Pentacyclic triterpenes. Part 3: Synthesis and biological evaluation of oleanolic acid derivatives as novel inhibitors of glycogen phosphorylase. Bioorg. Med. Chem. Lett., 2006 16, (11), 2915-2919.
20. Chen, J; Gong, YC; Liu, J; Hua, WY; Zhang, LY; Sun, HB. Synthesis and biological evaluation of novel pyrazolo[4,3-b]oleanane derivatives as inhibitors of glycogen phosphorylase. Chem. Biodivers., 2008 5, (7), 1304-1312.
21. Zhang, YN; Zhang, W; Hong, D; Shi, L; Shen, Q; Li, JY; Li, J; Hu, LH. Oleanolic acid and its derivatives: New inhibitor of protein tyrosine phosphatase 1B with cellular activities. Bioorg. Med. Chem., 2008 16, (18), 8697-8705.
22. Ali, MS; Jahangir, M; ul Hussan, SS; Choudhary, MI. Inhibition of alpha-glucosidase by oleanolic acid and its synthetic derivatives. Phytochemistry, 2002 60, (3), 295-299.
23. Raphael, TJ; Kuttan, G. Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system. Phytomedicine, 2003 10, (6-7), 483-489.
24. Dat, NT; Lee, IS; Cai, XF; Shen, G; Kim, YH. Oleanane triterpenoids with inhibitory activity against NFAT transcription factor from Liquidambar formosana. Biol. Pharm. Bull., 2004 27, (3), 426-428.
25. Banno, N; Akihisa, T; Tokuda, H; Yasukawa, K; Higashihara, H; Ukiya, M; Watanabe, K; Kimura, Y; Hasegawa, J; Nishino, H. Triterpene acids from the leaves of Perilla frutescens and their anti-inflammatory and antitumor-promoting effects. Biosci. Biotech. Bioch., 2004 68, (1), 85-90.
26. Giner-Larza, EM; Manez, S; Recio, MC; Giner, RM; Prieto, JM; Cerda-Nicolas, M; Rios, JL. Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity. Eur. J. Pharmacol., 2001 428, (1), 137-143.
27. Ringbom, T; Segura, L; Noreen, Y; Perera, P; Bohlin, L. Ursolic acid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis. J. Nat. Prod., 1998 61, (10), 1212-1215.
28. Maia, JL; Lima-Junior, RCP; David, JP; David, JM; Santos, FA; Rao, VS. Oleanolic acid, a pentacyclic triterpene attenuates the mustard oil-induced colonic nociception in mice. Biol. Pharm. Bull., 2006 29, (1), 82-85.
29. Maia, JL; Lima-Junior, RCP; Melo, CM; David, JP; David, JM; Campos, AR; Santos, FA; Rao, VSN. Oleanolic acid, a pentacyclic triterpene attenuates capsaicin-induced nociception in mice: Possible mechanisms. Pharmacol. Res., 2006 54, (4), 282-286.
30. Astudillo, L; Rodriguez, JA; Schmeda-Hirschmann, G. Gastroprotective activity of oleanolic acid derivatives on experimentally induced gastric lesions in rats and mice. J. Pharm. Pharmacol., 2002 54, (4), 583-588.
31. Rodriguez, JA; Astudillo, L; Schmeda-Hirschmann, G. Oleanolic acid promotes healing of acetic acid-induced chronic gastric lesions in rats. Pharmacol. Res., 2003 48, (3), 291-294.
32. Sanchez, M; Theoduloz, C; Schmeda-Hitschmann, G; Razmilic, I; Yanez, T; Rodriguez, JA. Gastroprotective and ulcer-healing activity of oleanolic acid derivatives: In vitro-in vivo relationships. Life Sci., 2006 79, (14), 1349-1356.
33. Liu, J; Liu, YP; Klaassen, CD. Protective Effect of Oleanolic Acid against Chemical-Induced Acute Necrotic Liver-Injury in Mice. Acta Pharm. Sinic., 1995 16, (2), 97-102.
34. Yim, TK; Wu, WK; Pak, WF; Ko, KM. Hepatoprotective action of an oleanolic acid-enriched extract of Ligustrum lucidum fruits is mediated through an enhancement on hepatic glutathione regeneration capacity in mice. Phytother. Res., 2001 15, (7), 589-592.
35. Jeong, HG. Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury. Toxicol. Lett., 1999 105, (3), 215-222.
36. Kim, NY; Lee, MK; Park, MJ; Kim, SJ; Park, HJ; Choi, JW; Kim, SH; Cho, SY; Lee, JS. Momordin Ic and oleanolic acid from Kochiae fructus reduce carbon tetrachloride-induced hepatotoxicity in rats. J. Med. Food, 2005 8, (2), 177-183.
37. Liu, J; Liu, YP; Madhu, C; Klaassen, CD. Protective Effects of Oleanolic Acid on Acetaminophen-Induced Hepatotoxicity in Mice. J. Pharmacol. Exp. Ther., 1993 266, (3), 1607-1613.
38. Reisman, SA; Aleksunes, LM; Klaassen, CD. Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes. Biochem. Pharmacol., 2009 77, (7), 1273-1282.
39. Liu, YP; Kreppel, H; Liu, J; Choudhuri, S; Klaassen, CD. Oleanolic Acid Protects against Cadmium Hepatotoxicity by Inducing Metallothionein. J. Pharmacol. Exp. Ther., 1993 266, (1), 400-406.
40. Liu, J; Liu, YP; Parkinson, A; Klaassen, CD. Effect of Oleanolic Acid on Hepatic Toxicant-Activating and Detoxifying Systems in Mice. J. Pharmacol. Exp. Ther., 1995 275, (2), 768-774.
41. Liu, J; Wu, Q; Lu, YF; Pi, JB. New insights into generalized hepatoprotective effects of oleanolic acid: Key roles of metallothionein and Nrf2 induction. Biochem. Pharmacol., 2008 76, (7), 922-928.
42. Kim, KA; Lee, JS; Park, HJ; Kim, JW; Kim, CJ; Shim, IS; Kim, NJ; Han, SM; Lim, S. Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life Sci., 2004 74, (22), 2769-2779.
43. Zhu, YM; Shen, JK; Wang, HK; Cosentino, LM; Lee, KH. Synthesis and anti-HIV activity of oleanolic acid derivatives. Bioorg. Med. Chem. Lett., 2001 11, (24), 3115-3118.
44. Kashiwada, Y; Wang, HK; Nagao, T; Kitanaka, S; Yasuda, I; Fujioka, T; Yamagishi, T; Cosentino, LM; Kozuka, M; Okabe, K; Ikeshiro, Y; Hu, CQ; Yeh, E; Lee, KH. Anti-AIDS agents. 30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids. J. Nat. Prod., 1998 61, (9), 1090-1095.
45. Kashiwada, Y; Nagao, T; Hashimoto, A; Ikeshiro, Y; Okabe, H; Cosentino, LM; Lee, KH. Anti-AIDS agents 38. Anti-HIV activity of 3-O-acyl ursolic acid derivatives. J. Nat. Prod., 2000 63, (12), 1619-1622.
46. Ma, CM; Nakamura, N; Hattori, M; Kakuda, H; Qiao, JC; Yu, HL. Inhibitory effects on HIV-1 protease of constituents from the wood of Xanthoceras sorbifolia. J. Nat. Prod., 2000 63, (2), 238-242.
47. Assefa, H; Nimrod, A; Walker, L; Sindelar, R. Synthesis and evaluation of potential complement inhibitory semisynthetic analogs of oleanolic acid. Bioorg. Med. Chem. Lett., 1999 9, (14), 1889-1894.
48. Assefa, H; Nimrod, A; Walker, L; Sindelar, R. Enantioselective synthesis and complement inhibitory assay of A/B-ring partial analogues of oleanolic acid. Bioorg. Med. Chem. Lett., 2001 11, (13), 1619-1623.
49. Li, J; Guo, WJ; Yang, QY. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. Wordl J. Gastroentero., 2002 8, (3), 493-495.
50. Tokuda, H; Ohigashi, H; Koshimizu, K; Ito, Y. Inhibitory Effects of Ursolic and Oleanolic Acid on Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate. Cancer Lett., 1986 33, (3), 279-285.
51. Oguro, T; Liu, J; Klaassen, CD; Yoshida, T. Inhibitory effect of oleanolic acid on 12-O-tetradecanoylphorbol-13-acetate-induced gene expression in mouse skin. Toxicol. Sci., 1998 45, (1), 88-93.
52. Lee, HY; Chung, HY; Kim, KH; Lee, JJ; Kim, KW. Induction of Differentiation in the Cultured F9 Teratocarcinoma Stem-Cells by Triterpene Acids. J. Cancer Res. Clin., 1994 120, (9), 513-518.
53. Shon, KH; Lee, HY; Chung, HY; Young, HS; Yi, SY; Kim, KW. Anti-Angiogenic Activity of Triterpene Acids. Cancer Lett., 1995 94, (2), 213-218.
54. Muto, Y; Ninomiya, M; Fujiki, H. Present Status of Research on Cancer Chemoprevention in Japan. Jpn J. Clin. Oncol., 1990 20, (3), 219-224.
55. Liu, YG. US4675318. 1987.
56. Juan, ME; Wenzel, U; Ruiz-Gutierrez, V; Daniel, H; Planas, JM. Olive fruit extracts inhibit proliferation and induce apoptosis in HT-29 human colon cancer cells. J. Nutr., 2006 136, (10), 2553-2557.
57. Kim, YK; Yoon, SK; Ryu, SY. Cytotoxic triterpenes from stem bark of Physocarpus intermedius. Planta Medica, 2000 66, (5), 485-486.
58. Juan, ME; Planas, JM; Ruiz-Gutierrez, V; Daniel, H; Wenzel, U. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Brit. J. Nutr., 2008 100, (1), 36-43.
59. Gao, Z; Maloney, DJ; Dedkova, LM; Hecht, SM. Inhibitors of DNA polymerase beta: Activity and mechanism. Bioorg. Med. Chem., 2008 16, (8), 4331-4340.
60. Amico, V; Barresi, V; Chillemi, R; Condorelli, DF; Sciuto, S; Spatafora, C; Tringali, C. Bioassay-Guided Isolation of Antiproliferative Compounds from Grape (Vitis vinifera) Stems. Nat. Prod. Comm., 2009 4, (1), 27-34.
61. Paszel, A; Hofmann, J; Zaprutko, L; Bednarczyk-Cwynar, B; Bock, G; Rybczynska, M. Antitumor activity and reversal of multidrug resistance by the newly synthesised oleanolic acid derivative-methyl-3,11-dioxoolean-12en-28-oate. Ejc Supplements, 2007 5, (4), 115-115.
62. Chiang, LC; Chiang, W; Chang, MY; Ng, LT; Lin, CC. Antileukemic activity of selected natural products in Taiwan. Am. J. Chinese Med., 2003 31, (1), 37-46.
63. Cipak, L; Grausova, L; Miadokova, E; Novotny, L; Rauko, P. Dual activity of triterpenoids: apoptotic versus antidifferentiation effects. Arch. Toxicol., 2006 80, (7), 429-435.
64. Lu, XM; Yi, HW; Xu, JL; Sun, Y; Li, JX; Cao, SX; Xu, Q. A novel synthetic oleanolic acid derivative with amino acid conjugate suppresses tumour growth by inducing cell cycle arrest. J. Pharm. Pharmacol., 2007 59, (8), 1087-1093.
65. Fernandes, J; Castilho, RO; da Costa, MR; Wagner-Souza, K; Kaplan, MAC; Gattass, CR. Pentacyclic triterpenes from Chrysobalanaceae species: cytotoxicity on multidrug resistant and sensitive leukemia cell lines. Cancer Lett., 2003 190, (2), 165-169.
66. Martin, R; Carvalho, J; Ilbeas, E; Hernandez, M; Ruiz-Gutierrez, V; Nieto, ML. Acidic triterpenes compromise growth and survival of astrocytoma cell lines by regulating reactive oxygen species accumulation. Cancer Res., 2007 67, (8), 3741-3751.
67. Wang, F; Hua, HM; Pei, YH; Chen, D; Jing, YK. Triterpenoids from the resin of Styrax tonkinensis and their antiproliferative and differentiation effects in human leukemia HL-60 cells. J. Nat. Prod., 2006 69, (5), 807-810.
68. Finlay, HJ; Honda, T; Gribble, GW; Danielpour, D; Benoit, NE; Suh, N; Williams, C; Sporn, MB. Novel A-ring cleaved analogs of oleanolic and ursolic acids which affect growth regulation in NRP.152 prostate cells. Bioorg. Med. Chem. Lett., 1997 7, (13), 1769-1772.
69. Hata, K; Hori, K; Takahashi, S. Differentiation-and Apoptosis-Inducing Activities by Pentacyclic Triterpenes on a Mouse Melanoma Cell Line. J. Nat. Prod., 2002 65, 645-648.
70. Noda, Y; Kaiya, T; Kohda, K; Kawazoe, Y. Enhanced cytotoxicity of some triterpenes toward leukemia L1210 cells cultured in low pH media: Possibility of a new mode of cell killing. Chem. Pharm. Bull., 1997 45, (10), 1665-1670.
71. Danielpour, D; Kadomatsu, K; Anzano, MA; Smith, M; Sporn, MB. Development and Characterization of Nontumorigenic and Tumorigenic Epithelial Cell Lines from Rat Dorsal-Lateral Prostate. Cancer Res., 1994 54, 3413-3421.
72. Danielpour, D. Induction of Transforming Growth Factor-beta Autocrine Activity by all-trans-Retinoic Acid and 1 alpha,25 Dihydroxyvitamin D3 in NRP-152 Rat Prostatic Epithelial Cells. J. Cell Physiol., 1996 166, 231-239.
73. Sporn, MB. Carcinogenesis and Cancer-Different Perspectives on the Same Disease. Cancer Res., 1991 51, (23), 6215-6218.
74. Hsu, HJ; Tsai, LH. The investigation of oleanolic acid and ursolic acid combined with high dose ionizing radiation on the apoptosis of HL-60 cells. Cancer Detect. Prev., 2000, 24 Suplement 21.
75. Folkman, J; Klagsbrun, M. Angiogenic Factors. Science, 1987 235, (4787), 442-447.
76. Liotta, LA; Kleinerm.J; Saidel, GM. Quantitative Relationships of Intravascular Tumor-Cells, Tumor Vessels, and Pulmonary Metastases Following Tumor Implantation. Cancer Res., 1974 34, (5), 997-1004.
77. Umehara, K; Takagi, R; Kuroyanagi, M; Ueno, A; Taki, T; Chen, YJ. Studies on Differentiation-Inducing Activities of Triterpenes. Chem. Pharm. Bull., 1992 40, (2), 401-405.
78. Marcinkiewicz, J; Grabowska, A; Chain, B. Nitric-Oxide up-Regulates the Release of Inflammatory Mediators by Mouse Macrophages. Eur. J. Immunol., 1995 25, (4), 947-951.
79. Choi, CY; You, HJ; Jeong, HG. Nitric oxide and tumor necrosis factor-alpha production by oleanolic acid via nuclear Factor-kappa B activation in macrophages. Biochem. Bioph. Res. Co., 2001 288, (1), 49-55.
80. Ahn, KS; Kim, JH; Oh, SR; Min, BS; Kinjo, J; Lee, HK. Effects of oleane-type triterpenoids from Fabaceous plants on the expression of ICAM-1 Biol. Pharm. Bull., 2002 25, (8), 1105-1107.
81. Gho, YS; Kleinnan, HK; Sosne, G. Angiogenic activity of human soluble intercellular adhesion molecule-1. Cancer Res., 1999 59, (20), 5128-5132.
82. Thomas, H; Coley, HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein. Cancer Control, 2003 10, 159-165.
83. Leonessa, F; Clarke, R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr. Relat. Cancer, 2003 10, 43-73.
84. Braga, F; Ayres-Saraiva, D; Gattass, CR; Capella, MAM. Oleanolic acid inhibits the activity of the multidrug resistance protein ABCC1 (MRP1) but not of the ABCB1 (P-glycoprotein): Possible use in cancer chemotherapy. Cancer Lett., 2007 248, (1), 147-152.
85. Dinkova-Kostova, AT; Liby, KT; Stephenson, KK; Holtzclaw, WD; Gao, XQ; Suh, N; Williarrli, C; Risingsong, R; Honda, T; Gribble, GW; Sporn, MB; Talalay, P. Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress. P. Natl. Acad. Sci. USA, 2005 102, (12), 4584-4589.
86. Guengerich, FP; Kim, DH; Iwasaki, M. Role of Human Cytochrome-P-450-Iie1 in the Oxidation of Many Low-Molecular-Weight Cancer Suspects. Chem Res. Toxicol., 1991 4, (2), 168-179.
87. Guengerich, FP; Shimada, T. Oxidation of Toxic and Carcinogenic Chemicals by Human Cytochrome-P-450 Enzymes. Chem Res. Toxicol., 1991 4, (4), 391-407.
88. Nebert, DW; McKinnon, RA; Puga, A. Human drug-metabolizing enzyme polymorphisms: Effects on risk of toxicity and cancer. DNA Cell Biol., 1996 15, (4), 273-280.
89. Tan, GT; Lee, SK; Lee, IS; Chen, JW; Leitner, P; Besterman, JM; Kinghorn, AD; Pezzuto, JM. Natural-product inhibitors of human DNA ligase I. Biochem. J., 1996 314, 993-1000.
90. Deng, JZ; Starck, SR; Hecht, SM. DNA polymerase beta inhibitors from Baeckea gunniana. J. Nat. Prod., 1999 62, (12), 1624-1626.
91. Deng, JZ; Starck, SR; Hecht, SM. Pentacyclic triterpenoids from Freziera sp that inhibit DNA polymerase beta. Bioorg. Med. Chem., 2000 8, (1), 247-250.
92. Uversky, VN; Narizhneva, NV; Ivanova, TV; Tomashevski, AY. Rigidity of human alpha-fetoprotein tertiary structure is under ligand control. Biochemistry, 1997 36, (44), 13638-13645.
93. Chaturvedula, VSP; Gao, ZJ; Hecht, SM; Jones, SH; Kingston, DGI. A new acylated oleanane triterpenoid from Couepia polyandra that inhibits the lyase activity of DNA polymerase beta. J. Nat. Prod., 2003 66, (11), 1463-1465.
94. Sporn, MB; Liby, KT. Cancer chemoprevention: scientific promise, clinical uncertainty. Nat. Clin. Pract. Oncol., 2005 2, (10), 518-525.
95. Yoshimi, N; Wang, AJ; Morishita, Y; Tanaka, T; Sugie, S; Kawai, K; Yamahara, J; Mori, H. Modifying Effects of Fungal and Herb Metabolites on Azoxymethane-Induced Intestinal Carcinogenesis in Rats. Jpn. J. Cancer Res., 1992 83, (12), 1273-1278.
96. Janakiram, NB; Indranie, C; Malisetty, SV; Jagan, P; Steele, VE; Rao, CV. Chemoprevention of Colon Carcinogenesis by Oleanolic Acid and Its Analog in Male F344 Rats and Modulation of COX-2 and Apoptosis in Human Colon HT-29 Cancer Cells. Pharmaceut. Res., 2008 25, (9), 2151-2157.
97. Kawamori, T; Tanaka, T; Hara, A; Yamahara, J; Mori, H. Modifying Effects of Naturally-Occurring Products on the Development of Colonic Aberrant Crypt Foci Induced by Azoxymethane in F344 Rats. Cancer Res., 1995 55, (6), 1277-1282.
98. Ito, Y; Yanase, S; Tokuda, H; Kishishita, M; Ohigashi, H; Hirota, M; Koshimizu, K. Epstein-Barr Virus-Activation by Tung Oil, Extracts of Aleurites-Fordii and Its Diterpene Ester 12-O-Hexadecanoyl-16-Hydroxyphorbol-13-Acetate. Cancer Lett., 1983 18, (1), 87-95.
99. Ohigashi, H; Takamura, H; Koshimizu, K; Tokuda, H; Ito, Y. Search for Possible Antitumor Promoters by Inhibition of 12-O-Tetradecanoylphorbol-13-Acetate-Induced Epstein-Barr Virus-Activation-Ursolic Acid and Oleanolic Acid from an Antiinflammatory Chinese Medicinal Plant, Glechoma-Hederaceae L. Cancer Lett., 1986 30, (2), 143-151.
100. Fukuda, Y; Sakai, K; Matsunaga, S; Tokuda, H; Tanaka, R. Cancer chemopreventive activity of lupane-and oleanane-type triterpenoids from the cones of Liquidamber styraciflua. Chem. Biodivers., 2005 2, (3), 421-428.
101. Shibata, S, Antitumor-promoting and anti-inflammatory activities of licorice principles and their modified compounds. Oxford University Press: 1994; Vol. 54, p 308-321.
102. Huang, MT; Ho, CT; Wang, ZY; Ferraro, T; Lou, YR; Stauber, K; Ma, W; Georgiadis, C; Laskin, JD; Conney, AH. Inhibition of Skin Tumorigenesis by Rosemary and Its Constituents Carnosol and Ursolic Acid. Cancer Res., 1994 54, (3), 701-708.
103. Boutwell, RK; Takiwaga, M; Verma, AK; Ashendel, CL. Observations on the mechanism of skin tumor promotion by phorbol esters. Princess Takamatsu Symp., 1983 14, 177-193.
104. Tseng, CP; Kim, YJ; Kumar, R; Verma, AK. Involvement of Protein-Kinase-C in the Transcriptional Regulation of 12-O-Tetradecanoylphorbol-13-Acetate-Inducible Genes Modulated by Ap-1 or Non-Ap-1 Transacting Factors. Carcinogenesis, 1994 15, (4), 707-711.
105. Resende, FA; Mattos de Andrade Barcala, CA; da Silva Faria, MC; Kato, FH; Cunha, WR; Tavares, DC. Antimutagenicity of ursolic acid and oleanolic acid against doxorubicin-induced clastogenesis in Balb/c mice. Life Sci., 2006 79, (13), 1268-1273.
106. Niikawa, M; Hayashi, H; Sato, T; Nagase, H; Kito, H. Isolation of Substances from Glossy Privet (Ligustrum-Lucidum Ait) Inhibiting the Mutagenicity of Benzo[a]Pyrene in Bacteria. Mutat. Res., 1993 319, (1), 1-9.
107. Ovesna, Z; Kozics, K; Slamenova, D. Protective effects of ursolic acid and oleanolic acid in leukemic cells. Mutat. Res.-Fund. Mol. M., 2006 600, (1-2), 131-137.
108. Hsu, HY; Yang, JJ; Lin, CC. Effects of oleanolic acid and ursolic acid on inhibiting tumor growth and enhancing the recovery of hematopoietic system postirradiation in mice. Cancer Lett., 1997 111, (1-2), 7-13.
109. Human, MI. Effects of oleanolic acid on experimental liver injury and therapeutic value in human hepatisis. Traditional Medicine (Zhong Chao Yao), 1997 8, 32-37.
110. Xu, WM; Liu, LZ; Loizidou, M; Ahmed, M; Charles, IG. The role of nitric oxide in cancer. Cell Research, 2002 12, (5-6), 311-320.
111. Mocellin, S; Bronte, V; Nitti, D. Nitric oxide, a double edged sword in cancer biology: Searching for therapeutic opportunities. Med. Res. Rev., 2007 27, (3), 317-352.
112. Huang, D; Ding, Y; Li, Y; Zhang, WM; Fang, WS; Chen, XG. Anti-tumor activity of a 3-oxo derivative of oleanolic acid. Cancer Lett., 2006 233, (2), 289-296.
113. Finlay, HJ; Honda, T; Gribble, GW. Synthesis of novel [3,2-b]indole fused oleanolic acids as potential inhibitors of cell proliferation. Arkivoc, 2002, 38-46.
114. Suh, N; Honda, T; Finlay, HJ; Barchowsky, A; Williams, C; Benoit, NE; Xie, QW; Nathan, C; Gribble, GW; Sporn, MB. Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res., 1998 58, (4), 717-723.
115. Chen, L; Zhang, YH; Kong, XW; Lan, E; Huang, ZJ; Peng, SX; Kaufman, DL; Tian, J. Design, synthesis, and antihepatocellular carcinoma activity of nitric oxide releasing derivatives of oleanolic acid. J. Med. Chem., 2008 51, (15), 4834-4838.
116. Chen, L; Zhang, YH; Kong, XW; Peng, SX; Tian, J. Synthesis and biological evaluation of nitric oxide-releasing derivatives of oleanolic acid as inhibitors of HepG2 cell apoptosis. Bioorg. Med. Chem. Lett., 2007 17, (11), 2979-2982.
117. Honda, T; Finlay, HJ; Gribble, GW; Suh, N; Sporn, MB. New enone derivatives of oleanolic acid and ursolic acid as inhibitors of nitric oxide production in mouse macrophages. Bioorg. Med. Chem. Lett., 1997 7, (13), 1623-1628.
118. Honda, T; Rounds, BV; Gribble, GW; Suh, NJ; Wang, YP; Sporn, MB. 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., 1998 8, (19), 2711-2714.
119. Honda, T; Rounds, BV; Bore, L; Favaloro, FG; Gribble, GW; Suh, N; Wang, YP; Sporn, MB. Novel synthetic oleanane triterpenoids: A series of highly active inhibitors of nitric oxide production in mouse macrophages. Bioorg. Med. Chem. Lett., 1999 9, (24), 3429-3434.
120. Honda, T; Rounds, BV; Bore, L; Finlay, HJ; Favaloro, FG; Suh, N; Wang, YP; Sporn, MB; Gribble, GW. 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., 2000 43, (22), 4233-4246.
121. Honda, T; Gribble, GW; Suh, N; Finlay, HJ; Rounds, BV; Bore, L; Favaloro, FG; Wang, YP; Sporn, MB. Novel synthetic oleanane and ursane triterpenoids with various enone functionalities in ring A as inhibitors of nitric oxide production in mouse macrophages. J. Med. Chem., 2000 43, (9), 1866-1877.
122. Honda, T; Honda, Y; Favaloro, FG; Gribble, GW; Suh, N; Place, AE; Rendi, MH; Sporn, MB. A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production. Bioorg. Med. Chem. Lett., 2002 12, (7), 1027-1030.
123. Honda, T; Janosik-, T; Honda, Y; Han, J; Liby, KT; Williams, CR; Couch, RD; Anderson, AC; Sporn, MB; Gribble, GW. Design, synthesis, and biological evaluation 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., 2004 47, (20), 4923-4932.
124. Place, AE; Suh, N; Williams, CR; Risingsong, R; Honda, T; Honda, Y; Gribble, GW; Leesnitzer, LM; Stimmel, JB; Willson, TM; Rosen, E; Sporn, MB. The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clin. Cancer Res., 2003 9, (7), 2798-2806.
125. Shishodia, S; Sethi, G; Konopleva, M; Andreeff, M; Aggarwal, BB. A synthetic triterpenoid, CDDO-Me, inhibits I kappa B alpha, kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappa B-regulated gene products in human leukemic cells. Clin. Cancer Res., 2006 12, (6), 1828-1838.
126. Yates, MS; Kwak, MK; Egner, PA; Groopman, JD; Bodreddigari, S; Sutter, TR; Baumgartner, KJ; Roebuck, BD; Liby, KT; Yore, MM; Honda, T; Gribble, GW; Sporn, MB; Kensler, TW. 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., 2006 66, (4), 2488-2494.
127. Ito, Y; Pandey, P; Sporn, MB; Datta, R; Kharbanda, S; Kufe, D. The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. Mol. Pharmacol., 2001 59, (5), 1094-1099.
128. Stadheim, TA; Suh, N; Ganju, N; Sporn, MB; Eastman, A. 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., 2002 277, (19), 16448-16455.
129. Zou, W; Liu, XG; Yue, P; Zhou, ZM; Sporn, MB; Lotan, R; Khuri, FR; Sun, SY. 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., 2004 64, (20), 7570-7578.
130. Ikeda, T; Nakata, Y; Kimura, F; Sato, K; Anderson, K; Motoyoshi, K; Sporn, M; Kufe, D. 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. Canc. Therapeut., 2004 3, (1), 39-45.
131. Hail, N; Konopleva, M; Sporn, M; Lotan, R; Andreeff, M. 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., 2004 279, (12), 11179-11187.
132. Hyer, ML; Croxton, R; Krajewska, M; Krajewski, S; Kress, CL; Lu, ML; Suh, N; Sporn, MB; Cryns, VL; Zapata, JM; Reed, JC. Synthetic triterpenoids cooperate with tumor necrosis factor-related apoptosis-inducing ligand to induce apoptosis of breast cancer cells. Cancer Res., 2005 65, (11), 4799-4808.
133. Gribble, GW; Honda, T; Sporn, M; Suh, N. WO 99/65478 1999.
134. Honda, T; Honda, Y; Gribble, GW; Sporn, M; Suh, N WO 2004/064723. 2004.
135. Sporn, M; Liby, K; Gribble, GW; Honda, T; Letterio, J WO 2008/136838. 2008.
136. Yang, L; Calingasan, N; Thomas, B; Chaturvedi, R; Kiaei, M; Wille, E; Liby, K; Williams, C; Royce, D; Risingsong, R; Musiek, E; Morrow, J; Sporn, M; Beal, M. Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLoS ONE, 2009 4, (6), e5757.
137. www.clinicaltrials.gov/ct2/show/NCT00550849.
138. www.clinicaltrials.gov/ct2/show/NCT00529113.
139. www.clinicaltrials.gov/ct2/show/NCT00508807.
140. www.cancer.gov/clinicaltrials/NCI-06-C-0151.
141. Suh, NJ; Wang, YP; Honda, T; Gribble, GW; Dmitrovsky, E; Hickey, WF; Maue, RA; Place, AE; Porter, DM; Spinella, MJ; Williams, CR; Wu, GF; Dannenberg, AJ; Flanders, KC; Letterio, JJ; Mangelsdorf, DJ; Nathan, CF; Nguyen, L; Porter, WW; Ren, RF; Roberts, AB; Roche, NS; Subbaramaiah, K; Sporn, MB. 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., 1999 59, (2), 336-341.
142. Konopleva, M; Zhang, WG; Shi, YX; McQueen, T; Tsao, T; Abdelrahim, M; Munsell, MF; Johansen, M; Yu, DH; Madden, T; Safe, SH; Hung, MC; Andreeff, M. Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells. Mol. Canc. Therapeut., 2006 5, (2), 317-328.
143. Konopleva, M; Tsao, T; Estrov, Z; Lee, RM; Wang, RY; Jackson, CE; McQueen, T; Monaco, G; Munsell, M; Belmont, J; Kantarjian, H; Sporn, MB; Andreeff, M. 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., 2004 64, (21), 7927-7935.
144. Suh, WS; Kim, YS; Schimmer, AD; Kitada, S; Minden, M; Andreeff, M; Suh, N; Sporn, M; Reed, JC. Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL. Leukemia, 2003 17, (11), 2122-2129.
145. Melichar, B; Konopleva, M; Hu, W; Melicharova, K; Andreeff, M; Freedman, RS. 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., 2004 93, (1), 149-154.
146. Vene, R; Larghero, P; Arena, G; Sporn, MB; Albini, A; Tosetti, F. Glycogen synthase kinase 3 beta regulates cell death induced by synthetic triterpenoids. Cancer Res., 2008 68, (17), 6987-6996.
147. Deeb, D; Gao, X; Dulchavsky, SA; Gautam, SC. CDDO-Me induces apoptosis and inhibits Akt, mTOR and NF-kappa B signaling proteins in prostate cancer cells. Anticancer Res., 2007 27, (5A), 3035-3044.
148. Zhang, CL; Ni, X; Konopleva, M; Andreeff, M; Duvic, M. The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in mycosis fungoides/Sezary syndrome cells. J. Investig. Dermatol., 2004 123, (2), 380-387.
149. Brookes, PS; Morse, K; Ray, D; Tompkins, A; Young, SM; Hilchey, S; Salim, S; Konopleva, M; Andreeff, M; Phipps, R; Bernstein, SH. 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., 2007 67, (4), 1793-1802.
150. Ray, DM; Morse, KM; Hilchey, SP; Garcia, TM; Felgar, RE; Maggirwar, SB; Phipps, RP; Bernstein, SH. 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 gamma-independent pathway. Exp. Hematol., 2006 34, (9), 1202-1211.
151. Alabran, JL; Cheuk, A; Liby, K; Sporn, M; Khan, J; Letterio, J; Leskov, KS. Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO. Cancer Biol. Ther., 2008 7, (5), 709-717.
152. Chintharlapalli, S; Papineni, S; Konopleva, M; Andreef, M; Samudio, I; Safe, S. 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., 2005 68, (1), 119-128.
153. Kong, G; Wang, D; Wang, H; Wu, J; Bielawski, J; Konopleva, M; Andreeff, M; Ruvolo, PP; Maurer, BJ. Synthetic triterpenoids have cytotoxicity in pediatric acute lymphoblastic leukemia cell lines but cytotoxicity is independent of induced ceramide increase in MOLT-4 cells. Leukemia, 2008 22, (6), 1258-1262.
154. Suh, N; Roberts, AB; Reffey, SB; Miyazono, K; Itoh, S; ten Dijke, P; Heiss, EH; Place, AE; Risingsong, R; Williams, CR; Honda, T; Gribble, GW; Sporn, MB. Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling. Cancer Res., 2003 63, (6), 1371-1376.
155. Hussain, S; Hofseth, L; Harris, C. Radical causes of cancer. Nat. Rev. Cancer, 2003 3, (4), 276-285.
156. Liby, K; Hock, T; Yore, MM; Suh, N; Place, AE; Risingsong, R; Williams, CR; Royce, DB; Honda, T; Honda, Y; Gribble, GW; Hill-Kapturczak, N; Agarwal, A; Sporn, MB. The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res., 2005 65, (11), 4789-4798.
157. Slamon, DJ; Clark, GM; Wong, SG; Levin, WJ; Ullrich, A; McGuire, WL. Human-Breast Cancer-Correlation of Relapse and Survival with Amplification of the Her-2 Neu Oncogene. Science, 1987 235, (4785), 177-182.
158. Kurokawa, H; Lenferink, AEG; Simpson, JF; Pisacane, PI; Sliwkowski, MX; Forbes, JT; Arteaga, CL. Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-ovorexpresessed tamoxifen-resistant breast cancer cells. Cancer Res., 2000 60, (20), 5887-5894.
159. Konopleva, M; Elstner, E; McQueen, TJ; Tsao, T; Sudarikov, A; Hu, W; Schober, WD; Wang, RY; Chism, D; Kornblau, SM; Younes, A; Collins, SJ; Koeffler, HP; Andreeff, M. Peroxisome proliferator-activated receptor gamma and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias. Mol. Canc. Therapeut., 2004 3, (10), 1249-1262.
160. Koschmieder, S; D'Alo, F; Radomska, H; Schoneich, C; Chang, JS; Konopleva, M; Kobayashi, S; Levantini, E; Suh, N; Di Ruscio, A; Voso, MT; Watt, JC; Santhanam, R; Sargin, L; Kantarjian, H; Andreeff, M; Sporn, MB; Perrotti, D; Berdel, WE; Muller-Tidow, C; Serve, H; Tenen, DG. CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer-binding protein alpha. Blood, 2007 110, (10), 3695-3705.
161. Wang, YP; Porter, WW; Suh, NJ; Honda, T; Gribble, GW; Leesnitzer, LM; Plunket, KD; Mangelsdorf, DJ; Blanchard, SG; Willson, TM; Sporn, MB. 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., 2000 14, (10), 1550-1556.
162. Lapillonne, H; Konopleva, M; Tsao, T; Gold, D; McQueen, T; Sutherland, RL; Madden, T; Andreeff, M. 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., 2003 63, (18), 5926-5939.
163. Dragnev, KH; Pitha-Rowe, I; Ma, Y; Petty, WJ; Sekula, D; Murphy, B; Rendi, M; Suh, N; Desai, NB; Sporn, MB; Freemantle, SJ; Dmitrovsky, E. Specific chemopreventive agents trigger proteasomal degradation of G(1) cyclins: Implications for combination therapy. Clin. Cancer Res., 2004 10, (7), 2570-2577.
164. Ito, Y; Pandey, P; Place, A; Sporn, MB; Gribble, GW; Honda, T; Kharbanda, S; Kufe, D. 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., 2000 11, (5), 261-267.
165. Ikeda, T; Sporn, M; Honda, T; Gribble, GW; Kufe, D. The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance. Cancer Res., 2003 63, (17), 5551-5558.
166. Couch, RD; Ganem, NJ; Zhou, M; Popov, VM; Honda, T; Veenstra, TD; Sporn, MB; Anderson, AC. 2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oic acid disrupts microtubule polymerization: A possible mechanism contributing to apoptosis. Mol. Pharmacol., 2006 69, (4), 1158-1165.
167. Pedersen, IM; Kitada, S; Schimmer, A; Kim, Y; Zapata, JM; Charboneau, L; Rassenti, L; Andreeff, M; Bennett, F; Sporn, MB; Liotta, LD; Kipps, TJ; Reed, JC. The triterpenoid CDDO induces apoptosis in refractory CLL B cells. Blood, 2002 100, (8), 2965-2972.
168. Inoue, S; Snowden, RT; Dyer, MJS; Cohen, GM. CDDO induces apoptosis via the intrinsic pathway in lymphoid cells. Leukemia, 2004 18, (5), 948-952.
169. Chauhan, D; Li, G; Podar, K; Hideshima, T; Shringarpure, R; Catley, L; Mitsiades, C; Munshi, N; Tai, YT; Suh, N; Gribble, GW; Honda, T; Schlossman, R; Richardson, P; Sporn, MB; Anderson, KC. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Blood, 2004 103, (8), 3158-3166.
170. Kress, C; Konopleva, M; Martínez-Garcia, V; Krajewska, M; Sophie, L; Hyer, M; McQueen, T; M., A; Reed, J; Zapata, M. Triterpenoids Display Single Agent Anti-tumor Activity in a Transgenic Mouse Model of Chronic Lymphocytic Leukemia and Small B Cell Lymphoma. PLoS ONE, 2007 2, (6), e599.
171. Brookes, P; Tompkins, A; Morse, K; Hilchey, S; Salim, S; Ray, D; Phipps, R; Bernstein, SH. The triterpenoids 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and their imidazole (CDDO-Im) and dinitrile derivatives (DI-CDDO) elicit apoptosis through a novel mitochondrial pathway. Blood, 2005 106, (11), 2426.
172. Konopleva, M; Andreeff, M; Sporn, M WO 02/47611. 2003.
173. Tschopp, J; Irmler, M; Thome, M. Inhibition of Fas death signals by FLIPs. Curr. Opin. Immunol., 1998 10, (5), 552-558.
174. Kim, Y; Suh, N; Sporn, M; Reed, JC. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J. Biol. Chem., 2002 277, (25), 22320-22329.
175. Matsumoto, M; Minami, M; Takeda, K; Sakao, Y; Akira, S. Ectopic expression of CHOP (GADD153) induces apoptosis in M1 myeloblastic leukemia cells. Febs Lett., 1996 395, (2-3), 143-147.
176. Ikeda, T; Kimura, F; Nakata, Y; Sato, K; Ogura, K; Motoyoshi, K; Sporn, M; Kufe, D. Triterpenoid CDDO-Im downregulates PML/RAR alpha expression in acute promyelocytic leukemia cells. Cell Death Differ., 2005 12, (5), 523-531.
177. Mangelsdorf, DJ; Thummel, C; Beato, M; Herrlich, P; Schutz, G; Umesono, K; Blumberg, B; Kastner, P; Mark, M; Chambon, P; Evans, RM. The Nuclear Receptor Superfamily-the 2nd Decade. Cell, 1995 83, (6), 835-839.
178. Mangelsdorf, DJ; Evans, RM. The Rxr Heterodimers and Orphan Receptors. Cell, 1995 83, (6), 841-850.
179. Johansen, M; Kempen, E; Newman, R; Nguyen, J; Madden, T. Preclinical pharmacokinetics of oral and intravenous CDDO, a novel triterpenoid antitumor agent. Proc. Am. Assoc. Cancer Res., 2002 43, 591-591.
180. Yue, P; Zhou, ZM; Khuri, FR; Sun, SY. 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., 2006 5, (5), 492-497.
181. Kim, KB; Lotan, R; Yue, P; Sporn, MB; Suh, N; Gribble, GW; Honda, T; Wu, GS; Hong, WK; Sun, SY. 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. Canc. Therapeut., 2002 1, (3), 177-184.
182. Zou, W; Chen, SZ; Liu, XG; Yue, P; Sporn, MB; Khuri, FR; Sun, SY. 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., 2007 6, (10), 1614-1620.
183. Liby, K; Royce, D; CR, W; Risingsong, R; MM, Y; Honda, T; Gribble, G; Dmitrovsky, E; Sporn, T; Sporn, MB. The Synthetic Triterpenoids CDDO-Methyl Ester and CDDO-Ethyl Amide Prevent Lung Cancer Induced by Vinyl Carbamate in A/J Mice. Cancer Res., 2007 67, (6), 2414-2419.
184. Gao, X; Deeb, D; Jiang, H; Liu, Y; Dulchavsky, SA; Gautam, SC. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappa B and Notch1 signaling. J. Neurooncol., 2007 84, (2), 147-157.
185. Konopleva, M; Contractor, R; Kurinna, SM; Chen, W; Andreeff, M; Ruvolo, PP. The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells. Leukemia, 2005 19, (8), 1350-1354.
186. Konopleva, M; Tsao, T; Ruvolo, P; Stiouf, I; Estrov, Z; Leysath, CE; Zhao, SR; Harris, D; Chang, SR; Jackson, CE; Munsell, M; Suh, N; Gribble, G; Honda, T; May, WS; Sporn, MB; Andreeff, M. Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood, 2002 99, (1), 326-335.
187. Samudio, I; Konopleva, M; Pelicano, H; Huang, P; Frolova, O; Bornmann, W; Ying, YM; Evans, R; Contractor, R; Andreeff, M. 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., 2006 69, (4), 1182-1193.
188. Leist, M; Jaattela, M. Four deaths and a funeral:from caspases to alternative mechanisms. Nat. Rev. Mol. Cell Biol., 2001 2, 589-598.
189. Kroemer, G; Martin, S. Caspase-independent cell death. Na. Med., 2005 11, (725-730).
190. Jarvis, W; Fornari, F; Auer, K; Freemerman, A; Szabo, E; MJ, B. Coordinate regulation of stress-and mitogen-activated protein kinases in the apoptotic actions of ceramide and sphingosine. Mol. Pharmacol., 1997 52, 935-947.
191. Ruvolo, P. Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol. Res., 2003 47, 383-392.
192. Kim, S; Hahn, J; Min, Y. Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and down-regulation of a phosphatase, PAC1. Blood, 1999 93, 3893-3899.
193. Kornblau, S; Ruvolo, P; YH, Q. Expression and prognostic impact of ERK2, BCL-XL and PP2A in acute myelogenous leukemia (AML) Blood, 1999 94, 68-68.
194. Ahmad, R; Raina, D; Meyer, C; Kharbanda, S; Kufe, D. Triterpenoid CDDO-Me blocks the NF-kappa B pathway by direct inhibition of IKK beta on Cys-179. J. Biol. Chem., 2006 281, (47), 35764-35769.
195. Duan, ZF; Foster, R; Bell, DA; Mahoney, J; Wolak, K; Vaidya, A; Hampel, C; Lee, H; Seiden, MV. Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin. Cancer Res., 2006 12, (17), 5055-5063.
196. Nilsson, MB; Langley, RR; Fidler, IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res., 2005 65, (23), 10794-10800.
197. Silver, DL; Naora, H; Liu, JS; Cheng, WJ; Montell, DJ. Activated signal transducer and activator of transcription (STAT) 3: Localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res., 2004 64, (10), 3550-3558.
198. Ling, XY; Konopleva, M; Zeng, ZH; Ruvolo, V; Stephens, LC; Schober, W; McQueen, T; Dietrich, M; Madden, TL; Andreefe, M. 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., 2007 67, (9), 4210-4218.
199. Duan, ZF; Ames, RY; Ryan, M; Hornicek, FJ; Mankin, H; Seiden, MV. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemoth. Pharm., 2009 63, (4), 681-689.
200. Vannini, N; Lorusso, G; Cammarota, R; Barberis, M; Noonan, DM; Sporn, MB; Albini, A. The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol. Canc. Therapeut., 2007 6, (12), 3139-3146.
201. Meyer, C; Ferguson, D; Watkins, B; Fey, E; Sonis, S. RTA 401 (CDDO) and RTA 402 (CDDO-Me), promising new anti-cancer agents that also prevent oral mucositis. Ejc Supplements, 2006 4, (12), 533.
202. Liby, K; Risingsong, R; Royce, DB; Williams, CR; Yore, MM; Honda, T; Gribble, GW; Lamph, WW; Vannini, N; Sogno, I; Albini, A; Sporn, MB. Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268. Clin. Cancer Res., 2008 14, (14), 4556-4563.
203. Kral, R; Meyer, C; Abrahams, R. Rodent and primate toxicity studies of oral RTA 402 (CDDO-Me), a novel agent with anticancer and antimucositis activities. Clin. Cancer Res., 2005 11, (24), 9154S-9155S.
204. Riccioni, R; Senese, M; Diverio, D; Riti, V; Mariani, G; Boe, A; LoCoco, F; Foa, R; Peschle, C; Sporn, M; Testa, U. Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels. Leukemia Res., 2008 32, (8), 1244-1258.
205. Elsawa, SR; Novak, AJ; Grote, D; Konopleva, M; Andreeff, M; Witzig, TE; Ansell, SM. CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenstrom macroglobulinemia. Leukemia Res., 2008 32, (12), 1895-1902.
206. Samudio, I; Konopleva, M; Hail, N; Shi, YX; McQueen, T; Hsu, T; Evans, R; Honda, T; Gribble, GW; Sporn, M; Gilbert, HF; Safe, S; Andreeff, M. 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., 2005 280, (43), 36273-36282.
207. Han, SS; Peng, LP; Chung, ST; DuBois, W; Maeng, SH; Shaffer, AL; Sporn, MB; Janz, S. CDDO-imidazolide inhibits growth and survival of c-Myc-induced mouse B cell and plasma cell neoplasms. Mol.Cancer, 2006 5, (22).
208. Ji, Y; Lee, HJ; Goodman, C; Uskokovic, M; Liby, K; Sporn, M; Suh, N. The synthetic triterpenoid CDDO-imidazolide induces monocytic differentiation by activating the Smad and ERK signaling pathways in HL60 leukemia cells. Mol. Canc. Therapeut., 2006 5, (6), 1452-1458.
209. Liby, K; Voong, N; Williams, CR; Risingsong, R; Royce, DB; Honda, T; Gribble, GW; Sporn, MB; Letterio, JJ. The synthetic triterpenoid CDDO-imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells. Clin. Cancer Res., 2006 12, (14), 4288-4293.
210. Yore, MM; Liby, KT; Honda, T; Gribble, GW; Sporn, MB. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-kappa B activation through direct inhibition of I kappa B kinase beta. Mol. Canc. Therapeut., 2006 5, (12), 3232-3239.
211. Yates, MS; Tauchi, M; Katsuoka, F; Flanders, KC; Liby, KT; Honda, T; Gribble, GW; Johnson, DA; Johnson, JA; Burton, NC; Guilarte, TR; Yamamoto, M; Sporn, MB; Kensler, TW. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol. Canc. Therapeut., 2007 6, (1), 154-162.
212. Dinkova-Kostova, AT; Jenkins, SN; Wehage, SL; Huso, DL; Benedict, AL; Stephenson, KK; Fahey, JW; Liu, H; Liby, KT; Honda, T; Gribble, GW; Sporn, MB; Talalay, P. A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UV-irradiated mice. Biochem. Bioph. Res. Co., 2008 367, (4), 859-865.
213. Chwalek, M; Lalun, N; Bobichon, H; Ple, K; Voutquenne-Nazabadioko, L. Structure-activity relationships of some hederagenin diglycosides: Haemolysis, cytotoxicity and apoptosis induction. BBA-Gen. Subjects, 2006 1760, (9), 1418-1427.
214. Yan, MC; Liu, Y; Chen, H; Ke, Y; Xu, QC; Cheng, MS. Synthesis and antitumor activity of two natural N-acetylglucosamine-bearing triterpenoid saponins: Lotoidoside D and E. Bioorg. Med. Chem. Lett., 2006 16, (16), 4200-4204.
215. Cheng, MS; Yan, MC; Liu, Y; Zheng, LG; Liu, J. Synthesis of beta-hederin and Hederacolchiside A(1): triterpenoid saponins bearing a unique cytotoxicity-inducing disaccharide moiety. Carbohyd. Res., 2006 341, (1), 60-67.
216. Yan, MC; Liu, Y; Lu, WX; Wang, H; Sha, Y; Cheng, MS. Facile synthesis and cytotoxicity of triterpenoid saponins bearing a unique disaccharide moiety: hederacolchiside A(1) and its analogues. Carbohyd. Res., 2008 343, (4), 780-784.