Highlights of pentacyclic triterpenes in the cancer setting

Pentacyclic Triterpenes as Promising Agents in Cancer

Volumn , Issue , 2011, Pages 277-306

  Safe, Stephen ^a,b   Chadalapaka, Gayathri ^a   Jutooru, Indira ^a   Chintharlapalli, Sudhakar ^a,b   Papineni, Sabitha ^a,b  

^a TEXAS A AND M UNIVERSITY   (United States)

^b TEXAS A AND M HEALTH SCIENCE CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84892053128     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter

References (154)

1. Newman D. J., Cragg G. M. & Snader K. M. (2000). The influence of natural products upon drug discovery. Nat. Prod. Rep. 17:215-234.
2. Buss A. D., Cox B. & Waigh R. D. (2003). Natural products as leads for new pharmaceuticals. In: D. J. Abraham (Ed.), Burgers' Medicinal Chemistry and Drug Discovery; Volume1: Drug Discovery, (pp 847-900). Hoboken, NJ: Wiley.
3. Grabley S. & Thiericke R. (1999). The impact of natural products on drug discovery. In: S. Grabley & R. Thiericke (Eds.), Drug Discovery from Nature, (pp 3-37). Berlin: Springer.
4. Newman D. J., Cragg G. M. & Snader K. M. (2003). Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod. 66:1022-1037.
5. Butler M. S. (2004). The role of natural product chemistry in drug discovery. J. Nat. Prod. 67:2141-2153.
6. Koehn F. E. & Carter G. T. (2005). The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 4:206-220.
7. HemaIswarya S. & Doble M. (2006). Potential synergism of natural products in the treatment of cancer. Phytother. Res. 20:239-249.
8. Lax E. (2004). The Mold in Dr. Florey's Coat. New York: Henry Holt Publishers.
9. Wainwright M. (1990). Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics. Oxford, UK: Blackwell.
10. Mann J. (1999). The Elusive Magic Bullet: The Search for the Perfect Drug. Oxford, UK: Oxford University Press.
11. Brown A. G., Smale T. C., King T. J., Hasenkamp R. & Thompson R. H. (1976). Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum. J. Chem. Soc. [Perkin 1] 1165-1170.
12. Tobert J. A. (2003). Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat. Rev. Drug Discov. 2:517-526.
13. (2006). Statins: the HMG CoA Reductase Inhibitors in Perspective. Oxford, UK: Taylor and Francis.
14. Cragg G. M., Newman D. J. & Snader K. M. (1997). Natural products in drug discovery and development. J. Nat. Prod. 60:52-60.
15. Proudfoot J. R. (2002). Drugs, leads, and drug-likeness: an analysis of some recently launched drugs. Bioorg. Med. Chem. Lett. 12:1647-1650.
16. Cragg G. M. & Newman D. J. (2005). Plants as a source of anti-cancer agents. J. Ethnopharmacol. 100:72-79.
17. Kingston D. G. I. (2005). Taxol and its analogs. In: G. M. Cragg, D. G. I. Kingston & D. J. Newman (Eds.), Anticancer Agents from Natural Products, (pp 89-122). Boca Raton, FL: Taylor & Francis.
18. Gueritte F. & Fahy J. (2005). The vinca alkaloids. In: G. M. Cragg, D. G. I. Kingston & D. J. Newman (Eds.), Anticancer Agents from Natural Products, (pp 123-136). Boca Raton, FL: Taylor & Francis.
19. Rahier N. J., Thomas C. J. & Hecht S. M. (2005). Camptothecin and its analogs. In: G. M. Cragg, D. G. I. Kingston & D. J. Newman (Eds.), Anticancer Agents from Natural Products, (pp 5-22). Boca Raton, FL: Taylor & Francis.
20. Murillo G. & Mehta R. G. (2001). Cruciferous vegetables and cancer prevention. Nutr. Cancer 41:17-28.
21. Kristal A. R. & Lampe J. W. (2002). Brassica vegetables and prostate cancer risk: a review of the epidemiological evidence. Nutr. Cancer 42:1-9.
22. Aggarwal B. B. & Ichikawa H. (2005). Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 4:1201-1215.
23. Broadbent T. A. & Broadbent H. S. (1998). . The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part II]. Curr. Med. Chem. 5:469-491.
24. Safe S., Papineni S. & Chintharlapalli S. (2008). Cancer chemotherapy with indole-3-carbinol, bis(3'-indolyl)methane and synthetic analogs. Cancer Lett. 269:326-338.
25. Sharma R. A., Gescher A. J. & Steward W. P. (2005). Curcumin: the story so far. Eur. J. Cancer 41:1955-1968.
26. Aggarwal B. B. & Shishodia S. (2006). Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol. 71:1397-1421.
27. Aggarwal B. B., Kumar A. & Bharti A. C. (2003). Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 23:363-398.
28. Cheng A. L., Hsu C. H., Lin J. K., Hsu M. M., Ho Y. F., Shen T. S., Ko J. Y., Lin J. T., Lin B. R., Ming-Shiang W., Yu H. S., Jee S. H., Chen G. S., Chen T. M., Chen C. A., Lai M. K., Pu Y. S., Pan M. H., Wang Y. J., Tsai C. C. & Hsieh C. Y. (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21:2895-2900.
29. Hayashi S., Watanabe J. & Kawajiri K. (1991). Genetic Polymorphisms in the 5'-Flanking Region Change Transcriptional Regulation of the Human Cytochrome P450IIE1 Gene. J. Biochem. (Tokyo) 110:559-565.
30. Sharma R. A., McLelland H. R., Hill K. A., Ireson C. R., Euden S. A., Manson M. M., Pirmohamed M., Marnett L. J., Gescher A. J. & Steward W. P. (2001). Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res. 7:1894-1900.
31. Sharma R. A., Euden S. A., Platton S. L., Cooke D. N., Shafayat A., Hewitt H. R., Marczylo T. H., Morgan B., Hemingway D., Plummer S. M., Pirmohamed M., Gescher A. J. & Steward W. P. (2004). Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res. 10:6847-6854.
32. Dhillon N., Wolff R. A. & Abbruzzese J. L. (2006). Phase II clinical trial of curcumin in patients with advanced pancreatic cancer. J. Clin. Oncol. 24:14151(Abstract).
33. Aggarwal S., Ichikawa H., Takada Y., Sandur S. K., Shishodia S. & Aggarwal B. B. (2006). Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkBa kinase and Akt activation. Mol. Pharmacol. 69:195-206.
34. Mohan R., Sivak J., Ashton P., Russo L. A., Pham B. Q., Kasahara N., Raizman M. B. & Fini M. E. (2000). Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B. J. Biol. Chem. 275:10405-10412.
35. Li L., Aggarwal B. B., Shishodia S., Abbruzzese J. & Kurzrock R. (2004). Nuclear factor-kB and IkB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis. Cancer 101:2351-2362.
36. Li L., Braiteh F. S. & Kurzrock R. (2005). Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 104:1322-1331.
37. Anto R. J., Mukhopadhyay A., Denning K. & Aggarwal B. B. (2002). Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 23:143-150.
38. Kunnumakkara A. B., Guha S., Krishnan S., Diagaradjane P., Gelovani J. & Aggarwal B. B. (2007). Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kB-regulated gene products. Cancer Res. 67:3853-3861.
39. Kamat A. M., Sethi G. & Aggarwal B. B. (2007). Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-kappaB and nuclear factor-kappaB-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells. Mol. Cancer Ther. 6:1022-1030.
40. Pae H. O., Jeong S. O., Jeong G. S., Kim K. M., Kim H. S., Kim S. A., Kim Y. C., Kang S. D., Kim B. N. & Chung H. T. (2007). Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells. Biochem. Biophys. Res. Commun. 353:1040-1045.
41. Kuo M. L., Huang T. S. & Lin J. K. (1996). Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. Biochim. Biophys. Acta 1317:95-100.
42. Han S. S., Chung S. T., Robertson D. A., Ranjan D. & Bondada S. (1999). Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin. Immunol. 93:152-161.
43. Xu R., Fazio G. C. & Matsuda S. P. (2004). On the origins of triterpenoid skeletal diversity. Phytochemistry 65:261-291.
44. Liu Y., Cai Y., Zhao Z., Wang J., Li J., Xin W., Xia G. & Xiang F. (2009). Cloning and functional analysis of a b-amyrin synthase gene associated with oleanolic acid biosynthesis in Gentiana straminea Maxim. Biol. Pharm. Bull. 32:818-824.
45. Shibuya M., Xiang T., Katsube Y., Otsuka M., Zhang H. & Ebizuka Y. (2007). Origin of structural diversity in natural triterpenes: direct synthesis of seco-triterpene skeletons by oxidosqualene cyclase. J. Am. Chem. Soc. 129:1450-1455.
46. Honda T., Gribble G. W., Suh N., Finlay H. J., Rounds B. V., Bore L., Favaloro F. G., Jr., Wang Y. & Sporn M. B. (2000). 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. 43:1866-1877.
47. Honda T., Finlay H. J., Gribble G. W., Suh N. & Sporn M. B. (1997). New enone derivatives of oleanolic acid and ursolic acid as inhibitors of nitric oxide production in mouse macrophages. Bioorg. Med. Chem. Lett. 7:1623-1628.
48. Honda T., Rounds B. V., Gribble G. W., Suh N., Wang Y. & Sporn M. B. (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.
49. Couch R. D., Browning R. G., Honda T., Gribble G. W., Wright D. L., Sporn M. B. & Anderson A. C. (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.
50. Chintharlapalli S., Papineni S., Jutooru I., McAlees A. & Safe S. (2007). Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor g (PPARg) agonists in colon cancer cells. Mol. Cancer Therap. 6:1588-1598.
51. Chadalapaka G., Jutooru I., McAlees A., Stefanac T. & Safe S. (2008). Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives. Bioorg. Med. Chem. Lett. 18:2633-2639.
52. Papineni S., Chintharlapalli S. & Safe S. (2008). Methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate is a peroxisome proliferator-activated receptor g agonist that induces receptor-independent apoptosis in LNCaP prostate cancer cells. Mol. Pharmacol. 73:553-565.
53. Chintharlapalli S., Papineni S., Liu S., Jutooru I., Chadalapaka G., Cho S. D., Murthy R., You Y. J. & Safe S. (2007). 2-Cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid, activates peroxisome proliferator-activated receptor g in colon and pancreatic cancer cells. Carcinogenesis 28:2337-2346.
54. Sun H. X., Zheng Q. F. & Tu J. (2006). Induction of apoptosis in HeLa cells by 3b-hydroxy-12-oleanen-27-oic acid from the rhizomes of Astilbe chinensis. Bioorg. Med. Chem. 14:1189-1198.
55. Zheng Q. F., Sun H. X., He Q. J. & Ye Y. P. (2006). Induction of apoptosis in HeLa cells by 3b-hydroxyurs-12-en-27-oic acid. Chem. Biodivers. 3:742-753.
56. Martin R., Carvalho-Tavares J., Ibeas E., Hernandez M., Ruiz-Gutierrez V. & Nieto M. L. (2007). Acidic triterpenes compromise growth and survival of astrocytoma cell lines by regulating reactive oxygen species accumulation. Cancer Res. 67:3741-3751.
57. Zhang P., Li H., Chen D., Ni J., Kang Y. & Wang S. (2007). Oleanolic acid induces apoptosis in human leukemia cells through caspase activation and poly(ADP-ribose) polymerase cleavage. Acta Biochim. Biophys. Sin. (Shanghai) 39:803-809.
58. Juan M. E., Planas J. M., Ruiz-Gutierrez V., Daniel H. & Wenzel U. (2008). Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br. J. Nutr. 100:36-43.
59. Juan M. E., Wenzel U., Ruiz-Gutierrez V., Daniel H. & Planas J. M. (2006). Olive fruit extracts inhibit proliferation and induce apoptosis in HT-29 human colon cancer cells. J. Nutr. 136:2553-2557.
60. Huang Y., Zhou Y., Fan Y. & Zhou D. (2008). Celastrol inhibits the growth of human glioma xenografts in nude mice through suppressing VEGFR expression. Cancer Lett. 264:101-106.
61. Yang H., Chen D., Cui Q. C., Yuan X. & Dou Q. P. (2006). Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res. 66:4758-4765.
62. Zhang T., Hamza A., Cao X., Wang B., Yu S., Zhan C. G. & Sun D. (2008). A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol. Cancer Ther. 7:162-170.
63. Abbas S., Bhoumik A., Dahl R., Vasile S., Krajewski S., Cosford N. D. & Ronai Z. A. (2007). Preclinical studies of celastrol and acetyl isogambogic acid in melanoma. Clin. Cancer Res. 13:6769-6778.
64. Sethi G., Ahn K. S., Pandey M. K. & Aggarwal B. B. (2007). Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-kB-regulated gene products and TAK1-mediated NF-kB activation. Blood 109:2727-2735.
65. Rabi T., Karunagaran D., Krishnan N. M. & Bhattathiri V. N. (2002). Cytotoxic activity of amooranin and its derivatives. Phytother. Res. 16 Suppl 1:S84-S86.
66. Rabi T. & Banerjee S. (2008). Novel synthetic triterpenoid methyl 25-hydroxy-3-oxoolean-12-en-28-oate induces apoptosis through JNK and p38 MAPK pathways in human breast adenocarcinoma MCF-7 cells. Mol. Carcinog. 47:415-423.
67. Rabi T., Wang L. & Banerjee S. (2007). Novel triterpenoid 25-hydroxy-3-oxoolean-12-en-28-oic acid induces growth arrest and apoptosis in breast cancer cells. Breast Cancer Res. Treat. 101:27-36.
68. Ramachandran C., Nair P. K., Alamo A., Cochrane C. B., Escalon E. & Melnick S. J. (2006). Anticancer effects of amooranin in human colon carcinoma cell line in vitro and in nude mice xenografts. Int. J. Cancer 119:2443-2454.
69. Ramachandran C., Rabi T., Fonseca H. B., Melnick S. J. & Escalon E. A. (2003). Novel plant triterpenoid drug amooranin overcomes multidrug resistance in human leukemia and colon carcinoma cell lines. Int. J. Cancer 105:784-789.
70. Sharma M., Sharma P. D., Bansal M. P. & Singh J. (2007). Synthesis, cytotoxicity, and antitumor activity of lantadene-A congeners. Chem. Biodivers. 4:932-939.
71. Sharma M., Sharma P. D. & Bansal M. P. (2008). Lantadenes and their esters as potential antitumor agents. J. Nat. Prod. 71:1222-1227.
72. Kaur J., Sharma M., Sharma P. D. & Bansal M. P. (2008). Chemopreventive activity of lantadenes on two-stage carcinogenesis model in Swiss albino mice: AP-1 (c-jun), NFkB (p65) and P53 expression by ELISA and immunohistochemical localization. Mol. Cell Biochem. 314:1-8.
73. Jo E. H., Kim S. H., Ra J. C., Kim S. R., Cho S. D., Jung J. W., Yang S. R., Park J. S., Hwang J. W., Aruoma O. I., Kim T. Y., Lee Y. S. & Kang K. S. (2005). Chemopreventive properties of the ethanol extract of chinese licorice (Glycyrrhiza uralensis) root: induction of apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells. Cancer Lett. 230:239-247.
74. Huang M. T., Ho C. T., Wang Z. Y., Ferraro T., Lou Y. R., Stauber K., Ma W., Georgiadis C., Laskin J. D. & Conney A. H. (1994). Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res. 54:701-708.
75. Yoshida M., Fuchigami M., Nagao T., Okabe H., Matsunaga K., Takata J., Karube Y., Tsuchihashi R., Kinjo J., Mihashi K. & Fujioka T. (2005). Antiproliferative constituents from Umbelliferae plants VII. Active triterpenes and rosmarinic acid from Centella asiatica. Biol. Pharm. Bull. 28:173-175.
76. Fernandes J., Weinlich R., Castilho R. O., Amarante-Mendes G. P. & Gattass C. R. (2007). Pomolic acid may overcome multidrug resistance mediated by overexpression of anti-apoptotic Bcl-2 proteins. Cancer Lett. 245:315-320.
77. Fernandes J., Weinlich R., Castilho R. O., Kaplan M. A., Amarante-Mendes G. P. & Gattass C. R. (2005). Pomolic acid triggers mitochondria-dependent apoptotic cell death in leukemia cell line. Cancer Lett. 219:49-55.
78. Xu Y., Ge R., Du J., Xin H., Yi T., Sheng J., Wang Y. & Ling C. 2009 Corosolic acid induces apoptosis through mitochondrial pathway and caspases activation in human cervix adenocarcinoma HeLa cells. Cancer Lett. in press.
79. Hsu Y. L., Kuo P. L., Lin L. T. & Lin C. C. (2005). Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells. J. Pharmacol. Exp. Ther. 313:333-344.
80. Gurfinkel D. M., Chow S., Hurren R., Gronda M., Henderson C., Berube C., Hedley D. W. & Schimmer A. D. (2006). Disruption of the endoplasmic reticulum and increases in cytoplasmic calcium are early events in cell death induced by the natural triterpenoid Asiatic acid. Apoptosis 11:1463-1471.
81. Park B. C., Bosire K. O., Lee E. S., Lee Y. S. & Kim J. A. (2005). Asiatic acid induces apoptosis in SK-MEL-2 human melanoma cells. Cancer Lett. 218:81-90.
82. Zhao W., Entschladen F., Liu H., Niggemann B., Fang Q., Zaenker K. S. & Han R. (2003). Boswellic acid acetate induces differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells. Cancer Detect. Prev. 27:67-75.
83. Lu M., Xia L., Hua H. & Jing Y. (2008). Acetyl-keto-b-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. Cancer Res. 68:1180-1186.
84. Yuan H. Q., Kong F., Wang X. L., Young C. Y., Hu X. Y. & Lou H. X. (2008). Inhibitory effect of acetyl-11-keto-b-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells. Biochem. Pharmacol. 75:2112-2121.
85. Liu J. J., Huang B. & Hooi S. C. (2006). Acetyl-keto-b-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells. Br. J. Pharmacol. 148:1099-1107.
86. Liu J. J., Nilsson A., Oredsson S., Badmaev V., Zhao W. Z. & Duan R. D. (2002). Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis 23:2087-2093.
87. Xia L., Chen D., Han R., Fang Q., Waxman S. & Jing Y. (2005). Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells. Mol. Cancer Ther. 4:381-388.
88. Jing Y., Nakajo S., Xia L., Nakaya K., Fang Q., Waxman S. & Han R. (1999). Boswellic acid acetate induces differentiation and apoptosis in leukemia cell lines. Leuk. Res. 23:43-50.
89. Kunnumakkara A. B., Nair A. S., Sung B., Pandey M. K. & Aggarwal B. B. (2009). Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol. Cancer Res. 7:118-128.
90. Liu J. J., Nilsson A., Oredsson S., Badmaev V. & Duan R. D. (2002). Keto-and acetyl-keto-boswellic acids inhibit proliferation and induce apoptosis in Hep G2 cells via a caspase-8 dependent pathway. Int. J. Mol. Med. 10:501-505.
91. Yogeeswari P. & Sriram D. (2005). Betulinic acid and its derivatives: a review on their biological properties. Curr. Med. Chem. 12:657-666.
92. Sami A., Taru M., Salme K. & Jari Y.-K. (2006). Pharmacological properties of the ubiquitous natural product betulin. Eur. J. Pharmacol. Sci. 29:1-13.
93. Fulda S. (2008). Betulinic acid for cancer treatment and prevention. Int. J. Mol. Sci. 9:1096-1107.
94. Pisha E., Chai H., Lee I. S., Chagwedera T. E., Farnsworth N. R., Cordell G. A., Beecher C. W., Fong H. H., Kinghorn A. D., Brown D. M. & . (1995). Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat. Med. 1:1046-1051.
95. Sawada N., Kataoka K., Kondo K., Arimochi H., Fujino H., Takahashi Y., Miyoshi T., Kuwahara T., Monden Y. & Ohnishi Y. (2004). Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. Br. J. Cancer 90:1672-1678.
96. Kasperczyk H., La Ferla-Bruhl K., Westhoff M. A., Behrend L., Zwacka R. M., Debatin K. M. & Fulda S. (2005). Betulinic acid as new activator of NF-kB: molecular mechanisms and implications for cancer therapy. Oncogene 24:6945-6956.
97. Fulda S. & Debatin K. M. (2005). Sensitization for anticancer drug-induced apoptosis by betulinic Acid. Neoplasia 7:162-170.
98. Fulda S., Jeremias I. & Debatin K. M. (2004). Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells. Oncogene 23:7611-7620.
99. Fulda S., Scaffidi C., Susin S. A., Krammer P. H., Kroemer G., Peter M. E. & Debatin K. M. (1998). Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J. Biol. Chem. 273:33942-33948.
100. Schmidt M. L., Kuzmanoff K. L., Ling-Indeck L. & Pezzuto J. M. (1997). Betulinic acid induces apoptosis in human neuroblastoma cell lines. Eur. J. Cancer 33:2007-2010.
101. Fulda S., Jeremias I., Steiner H. H., Pietsch T. & Debatin K. M. (1999). Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells. Int. J. Cancer 82:435-441.
102. Fulda S., Friesen C., Los M., Scaffidi C., Mier W., Benedict M., Nunez G., Krammer P. H., Peter M. E. & Debatin K. M. (1997). Betulinic acid triggers CD95 (APO-1/Fas)-and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res. 57:4956-4964.
103. Ehrhardt H., Fulda S., Fuhrer M., Debatin K. M. & Jeremias I. (2004). Betulinic acid-induced apoptosis in leukemia cells. Leukemia 18:1406-1412.
104. Tan Y., Yu R. & Pezzuto J. M. (2003). Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin. Cancer Res. 9:2866-2875.
105. Rieber M. & Rieber M. S. (2006). Signalling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status. Int. J. Cancer 118:1135-1143.
106. Sarek J., Klinot J., Dzubak P., Klinotova E., Noskova V., Krecek V., Korinkova G., Thomson J. O., Janost'akova A., Wang S., Parsons S., Fischer P. M., Zhelev N. Z. & Hajduch M. (2003). New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure-activity relationships. J. Med. Chem. 46:5402-5415.
107. Chintharlapalli S., Papineni S., Ramaiah S. K. & Safe S. (2007). Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res. 67:2816-2823.
108. Saleem M., Kaur S., Kweon M. H., Adhami V. M., Afaq F. & Mukhtar H. (2005). Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway. Carcinogenesis 26:1956-1964.
109. Murtaza I., Saleem M., Adhami V. M., Hafeez B. B. & Mukhtar H. (2009). Suppression of cFLIP by lupeol, a dietary triterpene, is sufficient to overcome resistance to TRAIL-mediated apoptosis in chemoresistant human pancreatic cancer cells. Cancer Res. 69:1156-1165.
110. Higuchi H., Grambihler A., Canbay A., Bronk S. F. & Gores G. J. (2004). Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1. J. Biol. Chem. 279:51-60.
111. He Q., Lee D. I., Rong R., Yu M., Luo X., Klein M., El-Deiry W. S., Huang Y., Hussain A. & Sheikh M. S. (2002). Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway. Oncogene 21:2623-2633.
112. Konopleva M., Tsao T., Ruvolo P., Stiouf I., Estrov Z., Leysath C. E., Zhao S., Harris D., Chang S., Jackson C. E., Munsell M., Suh N., Gribble G., Honda T., May W. S., Sporn M. B. & Andreeff M. (2002). Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood 99:326-335.
113. Ito Y., Pandey P., Sporn M. B., Datta R., Kharbanda S. & 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.
114. Kim K. B., Lotan R., Yue P., Sporn M. B., Suh N., Gribble G. W., Honda T., Wu G. S., Hong W. K. & Sun S. Y. (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.
115. Suh N., Roberts A. B., Birkey R. S., Miyazono K., Itoh S., ten D. P., Heiss E. H., Place A. E., Risingsong R., Williams C. R., Honda T., Gribble G. W. & Sporn M. B. (2003). Synthetic triterpenoids enhance transforming growth factor b/Smad signaling. Cancer Res. 63:1371-1376.
116. Hyer M. L., Shi R., Krajewska M., Meyer C., Lebedeva I. V., Fisher P. B. & Reed J. C. (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.
117. To C., Kulkarni S., Pawson T., Honda T., Gribble G. W., Sporn M. B., Wrana J. L. & Di Guglielmo G. M. (2008). The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid-imidazolide alters transforming growth factor b-dependent signaling and cell migration by affecting the cytoskeleton and the polarity complex. J. Biol. Chem. 283:11700-11713.
118. Ahmad R., Raina D., Meyer C., Kharbanda S. & Kufe D. (2006). Triterpenoid CDDO-Me blocks the NF-kB pathway by direct inhibition of IKKb on Cys-179. J. Biol. Chem. 281:35764-35769.
119. Couch R. D., Ganem N. J., Zhou M., Popov V. M., Honda T., Veenstra T. D., Sporn M. B. & Anderson A. C. (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.
120. Samudio I., Konopleva M., Pelicano H., Huang P., Frolova O., Bornmann W., Ying Y., Evans R., Contractor R. & 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.
121. Shishodia S., Sethi G., Konopleva M., Andreeff M. & Aggarwal B. B. (2006). A synthetic triterpenoid, CDDO-Me, inhibits IkBa kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kB-regulated gene products in human leukemic cells. Clin. Cancer Res. 12:1828-1838.
122. Vannini N., Lorusso G., Cammarota R., Barberis M., Noonan D. M., Sporn M. B. & Albini A. (2007). The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol. Cancer Ther. 6:3139-3146.
123. Deeb D., Gao X., Dulchavsky S. A. & Gautam S. C. (2008). CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kB and NF-kB-regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. J. Exp. Ther. Oncol. 7:31-39.
124. Chintharlapalli S., Papineni S., Abdelrahim M., Abudayyeh A., Wu F., Mertens-Talcott S. U., Vanderlaag K., Cho S. D., Smith 3rd R. & Safe S. 2009 Oncogenic microRNA-27a is a target for anticancer agent methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate in colon cancer cells. Int. J. Cancer 125:1965-1974.
125. Dynan W. S. & Tjian R. (1983). The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell 35:79-87.
126. Dynan W. S. & Tjian R. (1983). Isolation of transcription factors that discriminate between different promoters recognized by RNA polymerase II. Cell 32:669-680.
127. Bouwman P. & Philipsen S. (2002). Regulation of the activity of Sp1-related transcription factors. Mol. Cell. Endocrinol. 195:27-38.
128. Black A. R., Black J. D. & Azizkhan-Clifford J. (2001). Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer. J. Cell. Physiol. 188:143-160.
129. Suske G. (1999). The Sp-family of transcription factors. Gene 238:291-300.
130. Ammendola R., Mesuraca M., Russo T. & Cimino F. (1992). Sp1 DNA binding efficiency is highly reduced in nuclear extracts from aged rat tissues. J. Biol. Chem. 267:17944-17948.
131. Adrian G. S., Seto E., Fischbach K. S., Rivera E. V., Adrian E. K., Herbert D. C., Walter C. A., Weaker F. J. & Bowman B. H. (1996). YY1 and Sp1 transcription factors bind the human transferrin gene in an age-related manner. J. Gerontol. A Biol. Sci. Med. Sci. 51:B66-B75.
132. Oh J. E., Han J. A. & Hwang E. S. (2007). Downregulation of transcription factor, Sp1, during cellular senescence. Biochem. Biophys. Res. Commun. 353:86-91.
133. Safe S. & Abdelrahim M. (2005). Sp transcription factor family and its role in cancer. Eur. J. Cancer 41:2438-2448.
134. Wang L., Wei D., Huang S., Peng Z., Le X., Wu T. T., Yao J., Ajani J. & Xie K. (2003). Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin. Cancer Res. 9:6371-6380.
135. Yao J. C., Wang L., Wei D., Gong W., Hassan M., Wu T. T., Mansfield P., Ajani J. & Xie K. (2004). Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clin. Cancer Res. 10:4109-4117.
136. Shi Q., Le X., Abbruzzese J. L., Peng Z., Qian C. N., Tang H., Xiong Q., Wang B., Li X. C. & Xie K. (2001). Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res. 61:4143-4154.
137. Zannetti A., Del V. S., Carriero M. V., Fonti R., Franco P., Botti G., D'Aiuto G., Stoppelli M. P. & Salvatore M. (2000). Coordinate up-regulation of Sp1 DNA-binding activity and urokinase receptor expression in breast carcinoma. Cancer Res. 60:1546-1551.
138. Chiefari E., Brunetti A., Arturi F., Bidart J. M., Russo D., Schlumberger M. & Filetti S. (2002). Increased expression of AP2 and Sp1 transcription factors in human thyroid tumors: a role in NIS expression regulation? BMC. Cancer 2:35.
139. Hosoi Y., Watanabe T., Nakagawa K., Matsumoto Y., Enomoto A., Morita A., Nagawa H. & Suzuki N. (2004). Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int. J. Oncol. 25:461-468.
140. Mertens-Talcott S. U., Chintharlapalli S., Li X. & Safe S. (2007). The oncogenic microRNA-27a targets genes that regulate specificity protein (Sp) transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res. 67:11001-11011.
141. Lou Z., O'Reilly S., Liang H., Maher V. M., Sleight S. D. & Mccormick J. J. (2005). Down-regulation of overexpressed Sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res. 65:1007-1017.
142. Abdelrahim M., Samudio I., Smith R., Burghardt R. & Safe S. (2002). Small inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cells. J. Biol. Chem. 277:28815-28822.
143. Abdelrahim M., Smith III R., Burghardt R. & Safe S. (2004). Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res. 64:6740-6749.
144. Abdelrahim M., Baker C. H., Abbruzzese J. L., Sheikh-Hamad D., Liu S., Cho S. D., Yoon K. & Safe S. (2007). Regulation of vascular endothelial growth factor receptor-1 (VEGFR1) expression by specificity proteins 1, 3 and 4 in pancreatic cancer cells. Cancer Res. 67:3286-3294.
145. Abdelrahim M., Baker C. H., Abbruzzese J. L. & Safe S. (2006). Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J. Natl. Cancer Inst. 98:855-868.
146. Higgins K. J., Abdelrahim M., Liu S., Yoon K. & Safe S. (2006). Regulation of vascular endothelial growth factor receptor-2 expression in pancreatic cancer cells by Sp proteins. Biochem. Biophys. Res. Commun. 345:292-301.
147. Finkenzeller G., Sparacio A., Technau A., Marme D. & Siemeister G. (1997). Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression. Oncogene 15:669-676.
148. Li Y., Xie M., Yang J., Yang D., Deng R., Wan Y. & Yan B. (2006). The expression of antiapoptotic protein survivin is transcriptionally upregulated by DEC1 primarily through multiple sp1 binding sites in the proximal promoter. Oncogene 25:3296-3306.
149. Wu J., Ling X., Pan D., Apontes P., Song L., Liang P., Altieri D. C., Beerman T. & Li F. (2005). Molecular mechanism of inhibition of survivin transcription by the GC-rich sequence-selective DNA binding antitumor agent, hedamycin: evidence of survivin down-regulation associated with drug sensitivity. J. Biol. Chem. 280:9745-9751.
150. Martin B., Vaquero A., Priebe W. & Portugal J. (1999). Bisanthracycline WP631 inhibits basal and Sp1-activated transcription initiation in vitro. Nucleic Acids Res. 27:3402-3409.
151. Wei D., Wang L., He Y., Xiong H. Q., Abbruzzese J. L. & Xie K. (2004). Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res. 64:2030-2038.
152. Abdelrahim M. & Safe S. (2005). Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expession in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol. Pharmacol. 68:317-329.
153. Scott G. K., Mattie M. D., Berger C. E., Benz S. C. & Benz C. C. (2006). Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 66:1277-1281.
154. Tillotson L. G. (1999). RIN ZF, a novel zinc finger gene, encodes proteins that bind to the CACC element of the gastrin promoter. J. Biol. Chem. 274:8123-8128.