Natural Products as Mechanism-based Anticancer Agents: Sp Transcription Factors as Targets

Phytotherapy Research

Volumn 30, Issue 11, 2016, Pages 1723-1732

  Safe, Stephen ^a   Kasiappan, Ravi ^a  

^a TEXAS A AND M UNIVERSITY   (United States)

Author keywords

pro oncogenic genes; reactive oxygen species; Sp transcription factors

Indexed keywords

BETULIC ACID; CELASTROL; CURCUMIN; CYCLIN D1; CYTOSPORONE B; DNA TOPOISOMERASE INHIBITOR; ETOPOSIDE; FLAVOPIRIDOL; GROWTH FACTOR RECEPTOR; HOMOHARRINGTONINE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IRINOTECAN; NATURAL PRODUCT; PREGNANCY SPECIFIC BETA1 GLYCOPROTEIN; PROTEIN BCL 2; SURVIVIN; TENIPOSIDE; TOPOTECAN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR SP3; TRANSCRIPTION FACTOR SP4; UNCLASSIFIED DRUG; VINCRISTINE; ANTINEOPLASTIC AGENT; BIOLOGICAL PRODUCT; TRANSCRIPTION FACTOR SP;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BREAST CANCER; BRONCHUS CANCER; CAMPTOTHECA; CELL CYCLE ARREST; CELL CYCLE PROGRESSION; CELL GROWTH; CELL SURVIVAL; COLON CANCER; CORRELATION ANALYSIS; DNA CLEAVAGE; DNA REPLICATION; DRUG BIOAVAILABILITY; DRUG METABOLISM; DRUG SOLUBILITY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME STABILITY; HUMAN; LEUKEMIA; LUNG CANCER; LYMPHOMA; MICROTUBULE ASSEMBLY; MITOCHONDRIAL MEMBRANE POTENTIAL; NONHUMAN; OVARY CANCER; PHYTOCHEMISTRY; PODOPHYLLUM; PROSTATE CANCER; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; TESTIS CANCER; CHEMISTRY; METABOLISM;

ANTINEOPLASTIC AGENTS; BIOLOGICAL PRODUCTS; HUMANS; SP TRANSCRIPTION FACTORS;

EID: 84994026397     PISSN: 0951418X     EISSN: 10991573     Source Type: Journal    
DOI: 10.1002/ptr.5669     Document Type: Review

References (200)

1. Abdelrahim M, Baker CH, Abbruzzese JL, et al. 2007. Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. Cancer Res 67: 3286–3294.
2. Adrian GS, Seto E, Fischbach KS, et al. 1996. YY1 and Sp1 transcription factors bind the human transferrin gene in an age-related manner. J Gerontol A Biol Sci Med Sci 51: B66–75.
3. Aggarwal BB, Shishodia S. 2006. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71: 1397–1421.
4. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. 2006. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol 69: 195–206.
5. Alakurtti S, Makela T, Koskimies S, Yli-Kauhaluoma J. 2006. Pharmacological properties of the ubiquitous natural product betulin. Eur J Pharm Sci 29: 1–13.
6. Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H. 2007. RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 6: 793–810.
7. 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.
8. Anto RJ, Mukhopadhyay A, Denning K, Aggarwal BB. 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.
9. Barisic K, Kopic J. 2002. Heat shock proteins and their clinical relevance. Acta Pharm 52: 71–82.
10. Bedolla RG, Gong J, Prihoda TJ, et al. 2012. Predictive value of Sp1/Sp3/FLIP signature for prostate cancer recurrence. PLoS One 7: e44917.
11. Black AR, Black JD, Azizkhan-Clifford J. 2001. Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188: 143–160.
12. Borchardt JK. 2002. The beginnings of drug therapy: ancient Mesopotamian medicine. Drug News Perspect 15: 187–192.
13. Broadbent TA, Broadbent HS. 1998. 1–1. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part I]. Curr Med Chem 5: 337–352.
14. Butler MS. 2004. The role of natural product chemistry in drug discovery. J Nat Prod 67: 2141–2153.
15. Chadalapaka G, Jutooru I, Burghardt R, Safe S. 2010. Drugs that target specificity proteins downregulate epidermal growth factor receptor in bladder cancer cells. Mol Cancer Res 8: 739–750.
16. Chadalapaka G, Jutooru I, Chintharlapalli S, et al. 2008. Curcumin decreases specificity protein expression in bladder cancer cells. Cancer Res 68: 5345–5354.
17. Chadalapaka G, Jutooru I, Safe S. 2012. Celastrol decreases specificity proteins (Sp) and fibroblast growth factor receptor-3 (FGFR3) in bladder cancer cells. Carcinogenesis 33: 886–894.
18. Chadalapaka G, Jutooru I, Sreevalsan S, et al. 2013. Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors. Int J Cancer 132: 795–806.
19. Chae JI, Cho JH, Lee KA, et al. 2012. Role of transcription factor Sp1 in the quercetin-mediated inhibitory effect on human malignant pleural mesothelioma. Int J Mol Med 30: 835–841.
20. Chae JI, Jeon YJ, Shim JH. 2013. Downregulation of Sp1 is involved in honokiol-induced cell cycle arrest and apoptosis in human malignant pleural mesothelioma cells. Oncol Rep 29: 2318–2324.
21. Chae JI, Jeon YJ, Shim JH. 2014. Anti-proliferative properties of kahweol in oral squamous cancer through the regulation specificity protein 1. Phytother Res 28: 1879–1886.
22. Chainy GB, Manna SK, Chaturvedi MM, Aggarwal BB. 2000. Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis. Oncogene 19: 2943–2950.
23. Cheng AL, Hsu CH, Lin JK, et al. 2001. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21: 2895–2900.
24. Cheung KL, Khor TO, Huang MT, Kong AN. 2010. Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM. Carcinogenesis 31: 880–885.
25. Cheung KL, Khor TO, Kong AN. 2009. Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. Pharm Res 26: 224–231.
26. Chintharlapalli S, Papineni S, Abdelrahim M, et al. 2009. Oncogenic microRNA-27a is a target for anticancer agent methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate in colon cancer cells. Int J Cancer 125: 1965–1974.
27. Chintharlapalli S, Papineni S, Lee SO, et al. 2011a. Inhibition of pituitary tumor-transforming gene-1 in thyroid cancer cells by drugs that decrease specificity proteins. Mol Carcinog 50: 655–667.
28. Chintharlapalli S, Papineni S, Lei P, Pathi S, Safe S. 2011b. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer 11: 371.
29. Chintharlapalli S, Papineni S, Ramaiah SK, Safe S. 2007. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 67: 2816–2823.
30. Cho JH, Shin JC, Cho JJ, Choi YH, Shim JH, Chae JI. 2015. Esculetin (6,7-dihydroxycoumarin): a potential cancer chemopreventive agent through suppression of Sp1 in oral squamous cancer cells. Int J Oncol 46: 265–271.
31. Cho JJ, Chae JI, Yoon G, et al. 2014. Licochalcone A, a natural chalconoid isolated from Glycyrrhiza inflata root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma. Int J Oncol 45: 667–674.
32. Chou YC, Chang MY, Wang MJ, et al. 2015. Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. DOI:10.1002/tox.22224.
33. Colon J, Basha MR, Madero-Visbal R, et al. 2011. Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice. Invest New Drugs 29: 41–51.
34. Cragg G, Suffness M. 1988. Metabolism of plant-derived anticancer agents. Pharmacol Ther 37: 425–461.
35. Cragg GM, Grothaus PG, Newman DJ. 2009. Impact of natural products on developing new anti-cancer agents. Chem Rev 109: 3012–3043.
36. Cragg GM, Newman DJ. 2004. A tale of two tumor targets: topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy J Nat Prod 67: 232–244.
37. Cragg GM, Newman DJ. 2005. Plants as a source of anti-cancer agents. J Ethnopharmacol 100: 72–79.
38. Cragg GM, Newman DJ, Snader KM. 1997. Natural products in drug discovery and development. J Nat Prod 60: 52–60.
39. Dev S. 1999. Ancient-modern concordance in Ayurvedic plants: some examples. Environ Health Perspect 107: 783–789.
40. Dhillon N, Aggarwal BB, Newman RA, et al. 2008. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14: 4491–4499.
41. Dias MMD, Noratto G, Martino HSD, et al. 2014. Pro-apoptotic activities of polyphenolics from acai (Euterpe oleracea martius) in human SW-480 colon cancer cells. Nutr Cancer 66: 1394–1405.
42. Dong Q, Cai N, Tao T, et al. 2014. An axis involving SNAI1, microRNA-128 and SP1 modulates glioma progression. PLoS One 9: e98651.
43. Dynan WS, Tjian R. 1983. The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell 35: 79–87.
44. Ehrhardt H, Fulda S, Fuhrer M, Debatin KM, Jeremias I. 2004. Betulinic acid-induced apoptosis in leukemia cells. Leukemia 18: 1406–1412.
45. Essafi-Benkhadir K, Grosso S, Puissant A, et al. 2009. Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness. PLoS One 4: e4478.
46. Fabricant DS, Farnsworth NR. 2001. The value of plants used in traditional medicine for drug discovery. Environ Health Perspect 109(Suppl 1): 69–75.
47. Fang Y, Yu YH, Hou Q, et al. 2012. The Chinese herb isolate isorhapontigenin induces apoptosis in human cancer cells by down-regulating overexpression of antiapoptotic protein XIAP. J Biol Chem 287: 35234–35243.
48. Farnsworth NR, Akerele O, Bingel AS, Soejarto DD, Guo Z. 1985. Medicinal plants in therapy. Bull World Health Organ 63: 965–981.
49. Fulciniti M, Amin S, Nanjappa P, et al. 2011. Significant biological role of Sp1 transactivation in multiple myeloma. Clin Cancer Res 17: 6500–6509.
50. Fulda S. 2008. Betulinic acid for cancer treatment and prevention. Int J Mol Sci 9: 1096–1107.
51. Fulda S, Debatin KM. 2000. Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors. Med Pediatr Oncol 35: 616–618.
52. Fulda S, Friesen C, Los M, et al. 1997. Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res 57: 4956–4964.
53. Fulda S, Kroemer G. 2009. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov Today 14: 885–890.
54. Fulda S, Scaffidi C, Susin SA, et al. 1998. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem 273: 33942–33948.
55. Galgon T, Wohlrab W, Drager B. 2005. Betulinic acid induces apoptosis in skin cancer cells and differentiation in normal human keratinocytes. Exp Dermatol 14: 736–743.
56. Galluzzi L, Larochette N, Zamzami N, Kroemer G. 2006. Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25: 4812–4830.
57. Gandhy SU, Kim K, Larsen L, Rosengren RJ, Safe S. 2012. Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs. BMC Cancer 12: 564.
58. Ganguly A, Das B, Roy A, et al. 2007. Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase I-DNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death. Cancer Res 67: 11848–11858.
59. Gaur P, Prasad S. 2014. Alterations in the Sp1 binding and Fmr-1 gene expression in the cortex of the brain during maturation and aging of mouse. Mol Biol Rep 41: 6855–6863.
60. Geng Z, Rong Y, Lau BH. 1997. S-allyl cysteine inhibits activation of nuclear factor kappa B in human T cells. Free Radic Biol Med 23: 345–350.
61. Goel A, Aggarwal BB. 2010. Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer 62: 919–930.
62. Grabley S, Thiericke R. 1999. Bioactive agents from natural sources: trends in discovery and application. Adv Biochem Eng Biotechnol 64: 101–154.
63. Guan H, Cai J, Zhang N, et al. 2012. Sp1 is upregulated in human glioma, promotes MMP-2-mediated cell invasion and predicts poor clinical outcome. Int J Cancer 130: 593–601.
64. Gueritte F, Fahy J. 2005. The vinca alkaloids. In Anticancer Agents from Natural Products, Cragg GM, Kingston DGI, Newman DJ (eds). Taylor & Francis: Boca Raton, FL; 123–136.
65. Guo MM, Hu LH, Wang YQ, et al. 2013. miR-22 is down-regulated in gastric cancer, and its overexpression inhibits cell migration and invasion via targeting transcription factor Sp1. Med Oncol 30: 542.
66. Gupta P, Wright SE, Kim SH, Srivastava SK. 2014. Phenethyl isothiocyanate: a comprehensive review of anti-cancer mechanisms. Biochim Biophys Acta 1846: 405–424.
67. Gupta SC, Kim JH, Prasad S, Aggarwal BB. 2010. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metast Rev 29: 405–434.
68. Han SS, Chung ST, Robertson DA, 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.
69. Hansen LA, Sigman CC, Andreola F, Ross SA, Kelloff GJ, De Luca LM. 2000. Retinoids in chemoprevention and differentiation therapy. Carcinogenesis 21: 1271–1279.
70. He MF, Liu L, Ge W, et al. 2009. Antiangiogenic activity of Tripterygium wilfordii and its terpenoids. J Ethnopharmacol 121: 61–68.
71. Hedrick E, Cheng Y, Jin UH, Kim K, Safe S. 2016. Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are non-oncogene addiction genes in cancer cells. Oncotarget. DOI:10.18632/oncotarget.7925.
72. Hedrick E, Crose L, Linardic CM, Safe S. 2015. Histone deacetylase inhibitors inhibit rhabdomyosarcoma by reactive oxygen species-dependent targeting of specificity protein tanscription factors. Mol Cancer Ther 14: 2143–2153.
73. HemaIswarya S, Doble M. 2006. Potential synergism of natural products in the treatment of cancer. Phytother Res 20: 239–249.
74. Hieronymus H, Lamb J, Ross KN, et al. 2006. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 10: 321–330.
75. Hsu TI, Wang MC, Chen SY, et al. 2012. Sp1 expression regulates lung tumor progression. Oncogene 31: 3973–3988.
76. Huang PH, Wang D, Chuang HC, Wei S, Kulp SK, Chen CS. 2009. Alpha-tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis. Carcinogenesis 30: 1125–1131.
77. 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.
78. Jiang NY, Woda BA, Banner BF, Whalen GF, Dresser KA, Lu D. 2008. Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev 17: 1648–1652.
79. Jo GH, Kim GY, Kim WJ, Park KY, Choi YH. 2014. Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway. Int J Oncol 45: 1497–1506.
80. Jungert K, Buck A, von Wichert G, et al. 2007. Sp1 is required for transforming growth factor-beta-induced mesenchymal transition and migration in pancreatic cancer cells. Cancer Res 67: 1563–1570.
81. Jutooru I, Chadalapaka G, Lei P, Safe S. 2010a. Inhibition of NF-kappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J Biol Chem 285: 25332–25344.
82. Jutooru I, Chadalapaka G, Sreevalsan S, et al. 2010b. Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth. Exp Cell Res 316: 2174–2188.
83. Jutooru I, Guthrie AS, Chadalapaka G, et al. 2014. Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents. Mol Cell Biol 34: 2382–2395.
84. Kamat AM, Sethi G, Aggarwal BB. 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.
85. Kannaiyan R, Shanmugam MK, 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.
86. Kantarjian HM, O'Brien S, Anderlini P, Talpaz M. 1996. Treatment of myelogenous leukemia: current status and investigational options. Blood 87: 3069–3081.
87. Kasperczyk H, La Ferla-Bruhl K, Westhoff MA, et al. 2005. Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene 24: 6945–6956.
88. Kelland LR. 2000. Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. Expert Opin Investig Drugs 9: 2903–2911.
89. Kim GY, Kim JH, Ahn SC, et al. 2004a. Lycopene suppresses the lipopolysaccharide-induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen-activated protein kinases and nuclear factor-kappaB. Immunology 113: 203–211.
90. Kim K, Chadalapaka G, Pathi SS, et al. 2012. Induction of the transcriptional repressor ZBTB4 in prostate cancer cells by drug-induced targeting of microRNA-17-92/106b-25 clusters. Mol Cancer Ther 11: 1852–1862.
91. Kim SO, Chun KS, Kundu JK, Surh YJ. 2004b. Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expression and activation of NF-kappaB and p38 MAPK in mouse skin. Biofactors 21: 27–31.
92. Kinghorn AD, Chin YW, Swanson SM. 2009. Discovery of natural product anticancer agents from biodiverse organisms. Curr Opin Drug Discov Devel 12: 189–196.
93. Kingston DGI. 2005. Taxol and its analogs. In Anticancer Agents from Natrual Products, Cargg GM, Kingston DGI, Newman DJ (eds). Taylor & Francis: Boca Raton, FL; 89–122.
94. Koehn FE, Carter GT. 2005a. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4: 206–220.
95. Koehn FE, Carter GT. 2005b. Rediscovering natural products as a source of new drugs. Discov Med 5: 159–164.
96. Kojetin D, Wang Y, Kamenecka TM, Burris TP. 2011. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem Biol 6: 131–134.
97. Kong LM, Liao CG, Fei F, Guo X, Xing JL, Chen ZN. 2010. Transcription factor Sp1 regulates expression of cancer-associated molecule CD147 in human lung cancer. Cancer Sci 101: 1463–1470.
98. Kong LM, Liao CG, Zhang Y, et al. 2014. A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Res 74: 3764–3778.
99. Korner A, Mudduluru G, Manegold C, Allgayer H. 2010. Enzastaurin inhibits invasion and metastasis in lung cancer by diverse molecules. Br J Cancer 103: 802–811.
100. Kristal AR, Lampe JW. 2002. Brassica vegetables and prostate cancer risk: a review of the epidemiological evidence. Nutrition Cancer 42: 1–9.
101. Kumar A, Dhawan S, Aggarwal BB. 1998. Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) inhibits TNF-induced NF-kappaB activation, IkappaB degradation, and expression of cell surface adhesion proteins in human vascular endothelial cells. Oncogene 17: 913–918.
102. Kumar N, Solt LA, Wang Y, et al. 2010. Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology 151: 3015–3025.
103. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. 2007. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 67: 3853–3861.
104. Laudet V, Gronemeyer H. 2001. The Nuclear Receptors Factbooks. Academic: San Diego.
105. Lee HS, Park CK, Oh E, et al. 2013. Low SP1 expression differentially affects intestinal-type compared with diffuse-type gastric adenocarcinoma. PLoS One 8e55522:.
106. Lee JH, Koo TH, Yoon H, et al. 2006. Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid. Biochem Pharmacol 72: 1311–1321.
107. Lee K-H, Xiao Z. 2005. Podophyllotoxins and analogs. In Anticancer Agents from Natural Products, Cargg GM, Kingston DGI, Newaman DJ (eds). Taylor & Francis: Boca Raton, FL; 95–116.
108. Lee KA, Chae JI, Shim JH. 2012a. Natural diterpenes from coffee, cafestol and kahweol induce apoptosis through regulation of specificity protein 1 expression in human malignant pleural mesothelioma. J Biomed Sci 19.
109. Lee KA, Lee YJ, Ban JO, et al. 2012b. The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1. Int J Mol Med 30: 21–27.
110. Li B. 2008. On interest-oriented teaching method for the basic theories of traditional Chinese medicine. Zhong Xi Yi Jie He Xue Bao 6: 643–644.
111. Li L, Gao P, Li Y, et al. 2014. JMJD2A-dependent silencing of Sp1 in advanced breast cancer promotes metastasis by downregulation of DIRAS3. Breast Cancer Res Treat 147: 487–500.
112. Li Y, Zhang T. 2014. Targeting cancer stem cells by curcumin and clinical applications. Cancer Lett 346: 197–205.
113. Li YZ, Li CJ, Pinto AV, Pardee AB. 1999. Release of mitochondrial cytochrome C in both apoptosis and necrosis induced by beta-lapachone in human carcinoma cells. Mol Med 5: 232–239.
114. Liu LF. 1989. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58: 351–375.
115. Liu LF, Desai SD, Li TK, Mao Y, Sun M, Sim SP. 2000. Mechanism of action of camptothecin. Ann N Y Acad Sci 922: 1–10.
116. Liu S, Jutooru I, Lei P, Kim K, Lee SO, Brents LK, Prather PL, Safe SH. 2012. Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer. Mol Cancer Ther 11: 1421–1431.
117. Losiewicz MD, Carlson BA, Kaur G, Sausville EA, Worland PJ. 1994. Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem Biophys Res Commun 201: 589–595.
118. Lou Z, O'Reilly S, Liang H, Maher VM, Sleight SD, McCormick JJ. 2005. Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res 65: 1007–1017.
119. Manna SK, Mukhopadhyay A, Aggarwal BB. 2000. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164: 6509–6519.
120. Mao Y, Chen H, Lin Y, et al. 2013. MicroRNA-330 inhibits cell motility by downregulating Sp1 in prostate cancer cells. Oncol Rep 30: 327–333.
121. Maurer GD, Leupold JH, Schewe DM, et al. 2007. Analysis of specific transcriptional regulators as early predictors of independent prognostic relevance in resected colorectal cancer. Clin Cancer Res 13: 1123–1132.
122. Mertens-Talcott SU, Chintharlapalli S, Li X, Safe S. 2007. The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res 67: 11001–11011.
123. Mongan NP, Gudas LJ. 2007. Diverse actions of retinoid receptors in cancer prevention and treatment. Differentiation 75: 853–870.
124. Mukherjee R, Jaggi M, Rajendran P, et al. 2004. Betulinic acid and its derivatives as anti-angiogenic agents. Bioorg Med Chem Lett 14: 2181–2184.
125. Murillo G, Mehta RG. 2001. Cruciferous vegetables and cancer prevention. Nutr Cancer 41: 17–28.
126. Nagase M, Oto J, Sugiyama S, Yube K, Takaishi Y, Sakato N. 2003. Apoptosis induction in HL-60 cells and inhibition of topoisomerase II by triterpene celastrol. Biosci Biotechnol Biochem 67: 1883–1887.
127. Nair V, Pathi S, Jutooru I, et al. 2013. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis 34: 2870–2879.
128. Nam EH, Lee Y, Zhao XF, Park YK, Lee JW, Kim S. 2014. ZEB2-Sp1 cooperation induces invasion by upregulating cadherin-11 and integrin alpha5 expression. Carcinogenesis 35: 302–314.
129. Newman DJ, Cragg GM, Snader KM. 2000. The influence of natural products upon drug discovery. Nat Prod Rep 17: 215–234.
130. Newman DJ, Cragg GM, Snader KM. 2003. Natural products as sources of new drugs over the period 1981–2002. J Nat Prod 66: 1022–1037.
131. Noble RL. 1990. The discovery of the vinca alkaloids—chemotherapeutic agents against cancer. Biochem Cell Biol 68: 1344–1351.
132. Noratto GD, Jutooru I, Safe S, Angel-Morales G, Mertens-Talcott SU. 2013. The drug resistance suppression induced by curcuminoids in colon cancer SW-480 cells is mediated by reactive oxygen species-induced disruption of the microRNA-27a-ZBTB10-Sp axis. Mol Nutr Food Res 57: 1638–1648.
133. O'Hagan HM, Wang W, Sen S, et al. 2011. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG islands. Cancer Cell 20: 606–619.
134. Oh JE, Han JA, Hwang ES. 2007. Downregulation of transcription factor, Sp1, during cellular senescence. Biochem Biophys Res Commun 353: 86–91.
135. Pang X, Yi Z, Zhang J, et al. 2010. Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/mammalian target of rapamycin pathway. Cancer Res 70: 1951–1959.
136. Papineni S, Chintharlapalli S, Abdelrahim M, et al. 2009. Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met. Carcinogenesis 30: 1193–1201.
137. Park W, Amin AR, Chen ZG, Shin DM. 2013. New perspectives of curcumin in cancer prevention. Cancer Prev Res (Phila) 6: 387–400.
138. Pathi S, Jutooru I, Chadalapaka G, Nair V, Lee SO, Safe S. 2012. Aspirin inhibits colon cancer cell and tumor growth and downregulates specificity protein (Sp) transcription factors. PLoS One 7e48208:.
139. Pathi S, Li X, Safe S. 2014. Tolfenamic acid inhibits colon cancer cell and tumor growth and induces degradation of specificity protein (Sp) transcription factors. Mol Carcinog 53(Suppl 1): E53–61.
140. Pathi SS, Lei P, Sreevalsan S, Chadalapaka G, Jutooru I, Safe S. 2011. Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer 63: 1133–1142.
141. Piedrafita FJ, Pfahl M. 1997. Retinoid-induced apoptosis and Sp1 cleavage occur independently of transcription and require caspase activation. Mol Cell Biol 17: 6348–6358.
142. Pisha E, Chai H, Lee IS, et al. 1995. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1: 1046–1051.
143. Powolny AA, Singh SV. 2010. Differential response of normal (PrEC) and cancerous human prostate cells (PC-3) to phenethyl isothiocyanate-mediated changes in expression of antioxidant defense genes. Pharm Res 27: 2766–2775.
144. Proudfoot JR. 2002. Drugs, leads, and drug-likeness: an analysis of some recently launched drugs. Bioorg Med Chem Lett 12: 1647–1650.
145. Rahier NJ, Thomas CJ, Hecht SM. 2005. Camptothecin and its analogs. In Anticancer Agents from Natural Products, Caraggg GM, Kingston DGI, MNEwman DJ (eds). Taylor & Francis: Boca Raton, Fl; 5–22.
146. Rehm S, Devor DE. 1993. Acute effects of 4-ipomeanol on experimental lung tumors with bronchiolar or alveolar cell features in Syrian hamsters or C3H/HeNCr mice. J Cancer Res Clin Oncol 120: 41–50.
147. Rochette-Egly C, Germain P. 2009. Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs). Nucl Recept Signal 7e005:.
148. Safe S, Imanirad P, Sreevalsan S, Nair V, Jutooru I. 2014a. Transcription factor Sp1, also known as specificity protein 1 as a therapeutic target. Expert Opin Ther Targets 18: 759–769.
149. Safe S, Jin UH, Hedrick E, Reeder A, Lee SO. 2014b. Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol 28: 157–172.
150. 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.
151. Sahu RP, Srivastava SK. 2009. The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst 101: 176–193.
152. Salminen A, Lehtonen M, Paimela T, Kaarniranta K. 2010. Celastrol: molecular targets of thunder God vine. Biochem Biophys Res Commun 394: 439–442.
153. Shanmugam MK, Rane G, Kanchi MM, et al. 2015. The multifaceted role of curcumin in cancer prevention and treatment. Molecules 20: 2728–2769.
154. Sharma RA, Euden SA, Platton SL, et al. 2004. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 10: 6847–6854.
155. Sharma RA, McLelland HR, Hill KA, et al. 2001. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res 7: 1894–1900.
156. Shi Y. 2007. Orphan nuclear receptors in drug discovery. Drug Discov Today 12: 440–445.
157. Shishodia S, Aggarwal BB. 2004. Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem 279: 47148–47158.
158. Shishodia S, Aggarwal BB. 2006. Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, I kappa B kinase activation and NF-kappa B-regulated gene expression. Oncogene 25: 1463–1473.
159. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. 2003. Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 63: 4375–4383.
160. Sienel W, Polzer B, Elshawi K, et al. 2008. Cellular localization of EMMPRIN predicts prognosis of patients with operable lung adenocarcinoma independent from MMP-2 and MMP-9. Mod Pathol 21: 1130–1138.
161. Singh SV, Singh K. 2012. Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research. Carcinogenesis 33: 1833–1842.
162. Sonoda J, Pei L, Evans RM. 2008. Nuclear receptors: decoding metabolic disease. FEBS Lett 582: 2–9.
163. Soprano DR, Qin P, Soprano KJ. 2004. Retinoic acid receptors and cancers. Annu Rev Nutr 24: 201–221.
164. Sung B, Park B, Yadav VR, Aggarwal BB. 2010. Celastrol, a triterpene, enhances TRAIL-induced apoptosis through the down-regulation of cell survival proteins and up-regulation of death receptors. J Biol Chem 285: 11498–11507.
165. Suske G, Bruford E, Philipsen S. 2005. Mammalian SP/KLF transcription factors: bring in the family. Genomics 85: 551–556.
166. Takada Y, Aggarwal BB. 2003. Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: abrogation of cyclooxygenase-2 and matrix metalloprotease-9. J Immunol 171: 3278–3286.
167. Takada Y, Aggarwal BB. 2004. Flavopiridol inhibits NF-kappaB activation induced by various carcinogens and inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation: abrogation of cyclin D1, cyclooxygenase-2, and matrix metalloprotease-9. J Biol Chem 279: 4750–4759.
168. Takada Y, Andreeff M, Aggarwal BB. 2005a. Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase activation, causing inhibition of expression of NF-kappaB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood 106: 641–649.
169. Takada Y, Kobayashi Y, Aggarwal BB. 2005b. Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion. J Biol Chem 280: 17203–17212.
170. Takada Y, Murakami A, Aggarwal BB. 2005c. Zerumbone abolishes NF-kappaB and IkappaBalpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion. Oncogene 24: 6957–6969.
171. Tang NY, Huang YT, Yu CS, et al. 2011. Phenethyl isothiocyanate (PEITC) promotes G2/M phase arrest via p53 expression and induces apoptosis through caspase- and mitochondria-dependent signaling pathways in human prostate cancer DU 145 cells. Anticancer Res 31: 1691–1702.
172. Theodosiou M, Laudet V, Schubert M. 2010. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell Mol Life Sci 67: 1423–1445.
173. Trachootham D, Zhou Y, Zhang H, et al. 2006. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10: 241–252.
174. Vizcaino C, Mansilla S, Portugal J. 2015. Sp1 transcription factor: a long-standing target in cancer chemotherapy. Pharmacol Ther 152: 111–124.
175. Wang F, Ma YL, Zhang P, et al. 2013. SP1 mediates the link between methylation of the tumour suppressor miR-149 and outcome in colorectal cancer. J Pathol 229: 12–24.
176. Wang L, Wei D, Huang S, et al. 2003. Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res 9: 6371–6380.
177. Wang XB, Peng WQ, Yi ZJ, Zhu SL, Gan QH. 2007. Expression and prognostic value of transcriptional factor Sp1 in breast cancer. Ai Zheng 26: 996–1000.
178. Wang XN, Wu Q, Yang X, Zhang LS, Wu YP, Lu C. 2010. Effects of Celastrol on growth inhibition of U937 leukemia cells through the regulation of the Notch1/NF-kappaB signaling pathway in vitro. Chin J Cancer 29: 385–390.
179. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. 1971. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 93: 2325–2327.
180. Westerheide SD, Bosman JD, Mbadugha BN, et al. 2004. Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 279: 56053–56060.
181. Worland PJ, Kaur G, Stetler-Stevenson M, Sebers S, Sartor O, Sausville EA. 1993. Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells. Correlation with decreased H1 kinase activity. Biochem Pharmacol 46: 1831–1840.
182. Wu CL, Huang AC, Yang JS, et al. 2011. Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC)-mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of caspase-3, mitochondria dysfunction and nitric oxide (NO) in human osteogenic sarcoma U-2 OS cells. J Orthop Res 29: 1199–1209.
183. Xiao D, Lew KL, Zeng Y, et al. 2006. Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential. Carcinogenesis 27: 2223–2234.
184. Xiao D, Powolny AA, Moura MB, et al. 2010. Phenethyl isothiocyanate inhibits oxidative phosphorylation to trigger reactive oxygen species-mediated death of human prostate cancer cells. J Biol Chem 285: 26558–26569.
185. Xu C, Shen G, Chen C, Gelinas C, Kong AN. 2005. Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24: 4486–4495.
186. Yang F, Oz HS, Barve S, de Villiers WJ, McClain CJ, Varilek GW. 2001. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol 60: 528–533.
187. Yang H, Chen D, Cui QC, Yuan X, Dou QP. 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.
188. Yao JC, Wang L, Wei D, et al. 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.
189. Yogeeswari P, Sriram D. 2005. Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem 12: 657–666.
190. Yu HJ, Shin JA, Nam JS, Kang BS, Cho SD. 2013. Apoptotic effect of dibenzylideneacetone on oral cancer cells via modulation of specificity protein 1 and Bax. Oral Dis 19: 767–774.
191. Yuan W. 1988. [The formation and development of basic theories as an independent discipline in Chinese traditional medicine] (Chi). Zhonghua Yi Shi Za Zhi 18: 154–158.
192. Zhang D, Xu L, Cao F, et al. 2010. Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way. Cell Stress Chaperones 15: 939–946.
193. Zhang J, Zhu ZG, Ji J, et al. 2005. Transcription factor Sp1 expression in gastric cancer and its relationship to long-term prognosis. World J Gastroenterol 11: 2213–2217.
194. Zhao Y, Zhang W, Guo Z, et al. 2013. Inhibition of the transcription factor Sp1 suppresses colon cancer stem cell growth and induces apoptosis in vitro and in nude mouse xenografts. Oncol Rep 30: 1782–1792.
195. Zheng LD, Li D, Xiang X, et al. 2013. Methyl jasmonate abolishes the migration, invasion and angiogenesis of gastric cancer cells through down-regulation of matrix metalloproteinase 14. BMC Cancer 13:.
196. Zhou C, Ji J, Cai Q, et al. 2013. MTA2 promotes gastric cancer cells invasion and is transcriptionally regulated by Sp1. Mol Cancer 12: 102.
197. Zhou DC, Zittoun R, Marie JP. 1995. Homoharringtonine: an effective new natural product in cancer chemotherapy. Bull Cancer 82: 987–995.
198. Zhu H, Ding WJ, Wu R, et al. 2010a. Synergistic anti-cancer activity by the combination of TRAIL/APO-2 L and celastrol. Cancer Invest 28: 23–32.
199. Zhu H, Liu XW, Cai TY, et al. 2010b. Celastrol acts as a potent antimetastatic agent targeting beta1 integrin and inhibiting cell-extracellular matrix adhesion, in part via the p38 mitogen-activated protein kinase pathway. J Pharmacol Exp Ther 334: 489–499.
200. Zhu H, Liu XW, Ding WJ, et al. 2010c. Up-regulation of death receptor 4 and 5 by celastrol enhances the anti-cancer activity of TRAIL/Apo-2 L. Cancer Lett 297: 155–164.