Anticancer properties of indole compounds: Mechanism of apoptosis induction and role in chemotherapy

Current Drug Targets

Volumn 11, Issue 6, 2010, Pages 652-666

  Ahmad, Aamir ^a   Sakr, Wael A ^a   Rahman, K M Wahidur ^a  

^a WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Apoptosis; Chemosensitization; Diindolylmethane; Indole 3 carbinol; NF B; Survivin

Indexed keywords

3 INDOLEMETHANOL; 3,3' DIINDOLYLMETHANE; BUTYRIC ACID; CISPLATIN; CURCUMIN; DOCETAXEL; DOXORUBICIN; ERLOTINIB; GEMCITABINE; GENISTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; ISOFLAVONE DERIVATIVE; OXALIPLATIN; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; SURVIVIN; TAMOXIFEN; UROKINASE; UROKINASE RECEPTOR;

ABSENCE OF SIDE EFFECTS; ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; ARTICLE; BONE METASTASIS; BREAST CANCER; BREAST TUMOR; CANCER CELL CULTURE; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER RESEARCH; CANCER RESISTANCE; CANCER RISK; CELL CYCLE ARREST; CELL CYCLE REGULATION; CHEMOPROPHYLAXIS; CHEMOSENSITIZATION; CLINICAL TRIAL; COLON CANCER; COLON TUMOR; COLORECTAL CANCER; DIETARY INTAKE; DOSE RESPONSE; DRUG ABSORPTION; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG POTENTIATION; DRUG SAFETY; DRUG TOLERABILITY; HUMAN; LARYNX PAPILLOMATOSIS; LIVER CANCER; LUNG CANCER; MONOTHERAPY; NONHUMAN; PANCREAS CANCER; PLEIOTROPY; PROSTATE CANCER; SIGNAL TRANSDUCTION; STOMACH CANCER; UTERINE CERVIX CANCER;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; HUMANS; INDOLES; NEOPLASMS;

EID: 77953483368     PISSN: 13894501     EISSN: None     Source Type: Journal    
DOI: 10.2174/138945010791170923     Document Type: Article

References (221)

1. [1] Heber D, Bowerman S. Applying science to changing dietary patterns. J Nutr 2001; 131: 3078S-81S.
2. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996; 96: 1027-39.
3. Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett WC, Giovannucci EL. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J Natl Cancer Inst 1999; 91: 605-13.
4. Boone CW, Kelloff GJ, Malone WE. Identification of candidate cancer chemopreventive agents and their evaluation in animal models and human clinical trials: a review. Cancer Res 1990; 50: 2-9.
5. Oganesian A, Hendricks JD, Williams DE. Long term dietary indole-3-carbinol inhibits diethylnitrosamine-initiated hepatocar-cinogenesis in the infant mouse model. Cancer Lett 1997; 118: 87-94.
6. Jin L, Qi M, Chen DZ, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res 1999; 59: 3991-7.
7. He YH, Friesen MD, Ruch RJ, Schut HA. Indole-3-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) carcinogenesis: inhibition of PhIP-DNA adduct formation, acceleration of PhIP metabolism, and induction of cytochrome P450 in female F344 rats. Food Chem Toxicol 2000; 38: 15-23.
8. Kojima T, Tanaka T, Mori H. Chemoprevention of spontaneous endometrial cancer in female Donryu rats by dietary indole-3- carbinol. Cancer Res 1994; 54: 1446-9.
9. Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl 1997; 28-29: 111-6.
10. Yuan F, Chen DZ, Liu K, Sepkovic DW, Bradlow HL, Auborn K. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res 1999; 19: 1673-80.
11. Verhoeven DT, Verhagen H, Goldbohm RA, van den Brandt PA, van PG. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem Biol Interact 1997; 103: 79-129.
12. McNaughton SA, Marks GC. Development of a food composition database for the estimation of dietary intakes of glucosinolates, the biologically active constituents of cruciferous vegetables. Br J Nutr 2003; 90: 687-97.
13. Holst B, Williamson G. A critical review of the bioavailability of glucosinolates and related compounds. Nat Prod Rep 2004; 21: 425-47.
14. Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomarkers Prev 1998; 7: 1091-100.
15. Conaway CC, Getahun SM, Liebes LL, et al. Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli. Nutr Cancer 2000; 38: 168-78.
16. Rouzaud G, Young SA, Duncan AJ. Hydrolysis of glucosinolates to isothiocyanates after ingestion of raw or microwaved cabbage by human volunteers. Cancer Epidemiol Biomarkers Prev 2004; 13: 125-31.
17. Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P. Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism and excretion in humans. Cancer Epidemiol Biomarkers Prev 2001; 10: 501-8.
18. Johnson IT. Glucosinolates: bioavailability and importance to health. Int J Vitam Nutr Res 2002; 72: 26-31.
19. Ludikhuyze L, Ooms V, Weemaes C, Hendrickx M. Kinetic study of the irreversible thermal and pressure inactivation of myrosinase from broccoli (Brassica oleracea L. Cv. italica). J Agric Food Chem 1999; 47: 1794-800.
20. Smith TK, Mithen R, Johnson IT. Effects of Brassica vegetable juice on the induction of apoptosis and aberrant crypt foci in rat colonic mucosal crypts in vivo. Carcinogenesis 2003; 24: 491-5.
21. McDanell R, McLean AE, Hanley AB, Heaney RK, Fenwick GR. The effect of feeding brassica vegetables and intact glucosinolates on mixed-function-oxidase activity in the livers and intestines of rats. Food Chem Toxicol 1989; 27: 289-93.
22. Terry P, Wolk A, Persson I, Magnusson C. Brassica vegetables and breast cancer risk. JAMA 2001; 285: 2975-7.
23. van PG, Verhoeven DT, Verhagen H, Goldbohm RA. Brassica vegetables and cancer prevention. Epidemiology and mechanisms. Adv Exp Med Biol 1999; 472: 159-68.
24. Verhagen H, Poulsen HE, Loft S, van PG, Willems MI, van Bladeren PJ. Reduction of oxidative DNA-damage in humans by brussels sprouts. Carcinogenesis 1995; 16: 969-70.
25. Keck AS, Finley JW. Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Integr Cancer Ther 2004; 3: 5-12.
26. Grubbs CJ, Steele VE, Casebolt T, et al. Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res 1995; 15: 709-16.
27. Shertzer HG, Senft AP. The micronutrient indole-3-carbinol: implications for disease and chemoprevention. Drug Metabol Drug Interact 2000; 17: 159-88.
28. Grose KR, Bjeldanes LF. Oligomerization of indole-3-carbinol in aqueous acid. Chem Res Toxicol 1992; 5: 188-93.
29. Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci USA 1991; 88: 9543-7.
30. Dashwood RH, Fong AT, Arbogast DN, Bjeldanes LF, Hendricks JD, Bailey GS. Anticarcinogenic activity of indole-3-carbinol acid products: ultrasensitive bioassay by trout embryo microinjection. Cancer Res 1994; 54: 3617-9.
31. Stresser DM, Blanchard AP, Turner SD, et al. Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates. Drug Metab Dispos 2000; 28: 1440-8.
32. Anderton MJ, Manson MM, Verschoyle RD, et al. Pharmacokine- tics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin Cancer Res 2004; 10: 5233-41.
33. Asad SF, Singh S, Ahmad A, Hadi SM. Flavonoids: antioxidants in diet and potential anticancer agents. Med Sci Res 1998; 26: 723-8.
34. Takahashi N, Dashwood RH, Bjeldanes LF, Bailey GS, Williams DE. Regulation of hepatic cytochrome P4501A by indole-3- carbinol: transient induction with continuous feeding in rainbow trout. Food Chem Toxicol 1995; 33: 111-20.
35. Bonnesen C, Eggleston IM, Hayes JD. Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res 2001; 61: 6120-30.
36. Zhu CY, Loft S. Effect of chemopreventive compounds from Brassica vegetables on NAD(P)H:quinone reductase and induction of DNA strand breaks in murine hepa1c1c7 cells. Food Chem Toxicol 2003; 41: 455-62.
37. Nho CW, Jeffery E. Crambene, a bioactive nitrile derived from glucosinolate hydrolysis, acts via the antioxidant response element to upregulate quinone reductase alone or synergistically with indole-3-carbinol. Toxicol Appl Pharmacol 2004; 198: 40-8.
38. Chen YH, Dai HJ, Chang HP. Suppression of inducible nitric oxide production by indole and isothiocyanate derivatives from Brassica plants in stimulated macrophages. Planta Med 2003; 69: 696-700.
39. Raj MH, bd Elmageed ZY, Zhou J, et al. Synergistic action of dietary phyto-antioxidants on survival and proliferation of ovarian cancer cells. Gynecol Oncol 2008; 110: 432-8.
40. Lee SH, Kim JS, Yamaguchi K, Eling TE, Baek SJ. Indole-3- carbinol and 3,3'-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem Biophys Res Commun 2005; 328: 63-9.
41. Jeong WS, Keum YS, Chen C, et al. Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells. J Biochem Mol Biol 2005; 38: 167-76.
42. Wagner AE, Ernst I, Iori R, Desel C, Rimbach G. Sulforaphane but not ascorbigen, indole-3-carbinole and ascorbic acid activates the transcription factor Nrf2 and induces phase-2 and antioxidant enzymes in human keratinocytes in culture. Exp Dermatol 2010; 19:137-44.
43. Arnao MB, Sanchez-Bravo J, Acosta M. Indole-3-carbinol as a scavenger of free radicals. Biochem Mol Biol Int 1996; 39: 1125-34.
44. Donald S, Verschoyle RD, Greaves P, et al. Dietary agent indole-3- carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma. Int J Cancer 2004; 111: 961-7.
45. Benabadji SH, Wen R, Zheng JB, Dong XC, Yuan SG. Anticarcinogenic and antioxidant activity of diindolylmethane derivatives. Acta Pharmacol Sin 2004; 25: 666-71.
46. Kim YH, Kwon HS, Kim DH, et al. 3,3'-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Inflamm Bowel Dis 2009; 15: 1164-73.
47. Cho HJ, Seon MR, Lee YM, et al. 3,3'-Diindolylmethane suppresses the inflammatory response to lipopolysaccharide in murine macrophages. J Nutr 2008; 138: 17-23.
48. Fan S, Meng Q, Saha T, Sarkar FH, Rosen EM. Low concentrations of diindolylmethane, a metabolite of indole-3- carbinol, protect against oxidative stress in a BRCA1-dependent manner. Cancer Res 2009; 69: 6083-91.
49. Hadi SM, Asad SF, Singh S, Ahmad A. Putative mechanism for anticancer and apoptosis-inducing properties of plant-derived polyphenolic compounds. IUBMB Life 2000; 50: 167-71.
50. de la Lastra CA, Villegas I. Resveratrol as an antioxidant and pro- oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 2007; 35: 1156-60.
51. Shamim U, Hanif S, Ullah MF, Azmi AS, Bhat SH, Hadi SM. Plant polyphenols mobilize nuclear copper in human peripheral lymphocytes leading to oxidatively generated DNA breakage: implications for an anticancer mechanism. Free Radic Res 2008; 42: 764-72.
52. Rahman A, Fazal F, Greensill J, Ainley K, Parish JH, Hadi SM. Strand scission in DNA induced by dietary flavonoids: role of Cu(I) and oxygen free radicals and biological consequences of scission. Mol Cell Biochem 1992; 111: 3-9.
53. Lee-Hilz YY, Boerboom AM, Westphal AH, Berkel WJ, Aarts JM, Rietjens IM. Pro-oxidant activity of flavonoids induces EpRE- mediated gene expression. Chem Res Toxicol 2006; 19: 1499-505.
54. Khan NS, Ahmad A, Hadi SM. Anti-oxidant, pro-oxidant properties of tannic acid and its binding to DNA. Chem Biol Interact 2000; 125: 177-89.
55. Ahmad A, Farhan AS, Singh S, Hadi SM. DNA breakage by resveratrol and Cu(II): reaction mechanism and bacteriophage inactivation. Cancer Lett 2000; 154: 29-37.
56. Ahmad A, Syed FA, Singh S, Hadi SM. Prooxidant activity of resveratrol in the presence of copper ions: mutagenicity in plasmid DNA. Toxicol Lett 2005; 159: 1-12.
57. Heiss EH, Schilder YD, Dirsch VM. Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells. J Biol Chem 2007; 282: 26759-66.
58. Singh S, Asad SF, Ahmad A, Khan NU, Hadi SM. Oxidative DNA damage by capsaicin and dihydrocapsaicin in the presence of Cu(II). Cancer Lett 2001; 169: 139-46.
59. Ahsan H, Parveen N, Khan NU, Hadi SM. Pro-oxidant, anti- oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact 1999; 121: 161-75.
60. Azam S, Hadi N, Khan NU, Hadi SM. Prooxidant property of green tea polyphenols epicatechin and epigallocatechin-3-gallate: implications for anticancer properties. Toxicol In Vitro 2004; 18: 555-61.
61. Riby JE, Firestone GL, Bjeldanes LF. 3,3'-diindolylmethane reduces levels of HIF-1alpha and HIF-1 activity in hypoxic cultured human cancer cells. Biochem Pharmacol 2008; 75: 1858-67.
62. Kohl R, Zhou J, Brune B. Reactive oxygen species attenuate nitric- oxide-mediated hypoxia-inducible factor-1alpha stabilization. Free Radic Biol Med 2006; 40: 1430-42.
63. Stewart ZA, Westfall MD, Pietenpol JA. Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci 2003; 24: 139-45.
64. Maya-Mendoza A, Tang CW, Pombo A, Jackson DA. Mechanisms regulating S phase progression in mammalian cells. Front Biosci 2009; 14: 4199-213.
65. Rahman KM, Aranha O, Glazyrin A, Chinni SR, Sarkar FH. Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast cancer cells. Oncogene 2000; 19: 5764-71.
66. Rahman KM, Aranha O, Sarkar FH. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr Cancer 2003; 45: 101-12.
67. Rahman KM, Li Y, Sarkar FH. Inactivation of akt and NF-kappaB play important roles during indole-3-carbinol-induced apoptosis in breast cancer cells. Nutr Cancer 2004; 48: 84-94.
68. Rahman KW, Sarkar FH. Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3'-diindolylmethane- induced apoptosis in breast cancer cells. Cancer Res 2005; 65: 364-71.
69. Rahman KW, Li Y, Wang Z, Sarkar SH, Sarkar FH. Gene expression profiling revealed survivin as a target of 3,3'- diindolylmethane-induced cell growth inhibition and apoptosis in breast cancer cells. Cancer Res 2006; 66: 4952-60.
70. Telang NT, Katdare M, Bradlow HL, Osborne MP, Fishman J. Inhibition of proliferation and modulation of estradiol metabolism: novel mechanisms for breast cancer prevention by the phytochemical indole-3-carbinol. Proc Soc Exp Biol Med 1997; 216: 246-52.
71. Cover CM, Hsieh SJ, Tran SH, et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem 1998; 273: 3838-47.
72. Pietenpol JA, Stewart ZA. Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology 2002; 181-182: 475-81.
73. Hong C, Firestone GL, Bjeldanes LF. Bcl-2 family-mediated apoptotic effects of 3,3'-diindolylmethane (DIM) in human breast cancer cells. Biochem Pharmacol 2002; 63: 1085-97.
74. Hong C, Kim HA, Firestone GL, Bjeldanes LF. 3,3'- Diindolylmethane (DIM) induces a G(1) cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21(WAF1/CIP1) expression. Carcinogenesis 2002; 23: 1297-305.
75. Chinni SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH. Indole-3- carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 2001; 20: 2927-36.
76. Cover CM, Hsieh SJ, Cram EJ, et al. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res 1999; 59: 1244-51.
77. Stresser DM, Williams DE, Griffin DA, Bailey GS. Mechanisms of tumor modulation by indole-3-carbinol. Disposition and excretion in male Fischer 344 rats. Drug Metab Dispos 1995; 23: 965-75.
78. Tiwari RK, Guo L, Bradlow HL, Telang NT, Osborne MP. Selective responsiveness of human breast cancer cells to indole-3- carbinol, a chemopreventive agent. J Natl Cancer Inst 1994; 86: 126-31.
79. Riby JE, Chang GH, Firestone GL, Bjeldanes LF. Ligand- independent activation of estrogen receptor function by 3, 3'- diindolylmethane in human breast cancer cells. Biochem Pharmacol 2000; 60: 167-77.
80. Wang Z, Yu BW, Rahman KM, Ahmad F, Sarkar FH. Induction of growth arrest and apoptosis in human breast cancer cells by 3,3- diindolylmethane is associated with induction and nuclear localization of p27kip. Mol Cancer Ther 2008; 7: 341-9.
81. Firestone GL, Bjeldanes LF. Indole-3-carbinol and 3-3'- diindolylmethane antiproliferative signaling pathways control cell- cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr 2003; 133: 2448S-55S.
82. Brew CT, Aronchik I, Hsu JC, et al. Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int J Cancer 2006; 118: 857-68.
83. Moiseeva EP, Heukers R, Manson MM. EGFR and Src are involved in indole-3-carbinol-induced death and cell cycle arrest of human breast cancer cells. Carcinogenesis 2007; 28: 435-45.
84. Hsu JC, Dev A, Wing A, Brew CT, Bjeldanes LF, Firestone GL. Indole-3-carbinol mediated cell cycle arrest of LNCaP human prostate cancer cells requires the induced production of activated p53 tumor suppressor protein. Biochem Pharmacol 2006; 72: 1714-23.
85. Jump SM, Kung J, Staub R, et al. N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Biochem Pharmacol 2008; 75: 713-24.
86. Howells LM, Neal CP, Brown MC, Berry DP, Manson MM. Indole-3-carbinol enhances anti-proliferative, but not anti-invasive effects of oxaliplatin in colorectal cancer cell lines. Biochem Pharmacol 2008; 75: 1774-82.
87. Chinnakannu K, Chen D, Li Y, et al. Cell cycle-dependent effects of 3,3'-diindolylmethane on proliferation and apoptosis of prostate cancer cells. J Cell Physiol 2009; 219: 94-9.
88. Vivar OI, Lin CL, Firestone GL, Bjeldanes LF. 3,3'- Diindolylmethane induces a G(1) arrest in human prostate cancer cells irrespective of androgen receptor and p53 status. Biochem Pharmacol 2009; 78: 469-76.
89. Nguyen HH, Aronchik I, Brar GA, Nguyen DH, Bjeldanes LF, Firestone GL. The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing. Proc Natl Acad Sci USA 2008; 105: 19750-5.
90. Machijima Y, Ishikawa C, Sawada S, et al. Anti-adult T-cell leukemia/lymphoma effects of indole-3-carbinol. Retrovirology 2009; 6: 7.
91. Choi HJ, Lim dY, Park JH. Induction of G1 and G2/M cell cycle arrests by the dietary compound 3,3'-diindolylmethane in HT-29 human colon cancer cells. BMC Gastroenterol 2009; 9: 39.
92. Pappa G, Strathmann J, Lowinger M, Bartsch H, Gerhauser C. Quantitative combination effects between sulforaphane and 3,3'- diindolylmethane on proliferation of human colon cancer cells in vitro. Carcinogenesis 2007; 28: 1471-7.
93. Sarkar FH, Rahman KM, Li Y. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3- carbinol (I3C) treatment of breast cancer cells. J Nutr 2003; 133: 2434S-9S.
94. Li Y, Li X, Sarkar FH. Gene expression profiles of I3C- and DIM- treated PC3 human prostate cancer cells determined by cDNA microarray analysis. J Nutr 2003; 133: 1011-9.
95. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 2005; 4: 1201-15.
96. Cotter TG. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer 2009; 9: 501-7.
97. Sarkar FH, Li Y. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics. Cancer Treat Rev 2009; 35: 597-607.
98. Sarkar FH, Li Y, Wang Z, Kong D. Cellular signaling perturbation by natural products. Cell Signal 2009; 21: 1541-7.
99. Moiseeva EP, Almeida GM, Jones GD, Manson MM. Extended treatment with physiologic concentrations of dietary phytochemi- cals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol Cancer Ther 2007; 6: 3071-9.
100. Howells LM, Gallacher-Horley B, Houghton CE, Manson MM, Hudson EA. Indole-3-carbinol inhibits protein kinase B/Akt and induces apoptosis in the human breast tumor cell line MDA MB468 but not in the nontumorigenic HBL100 line. Mol Cancer Ther 2002; 1: 1161-72.
101. Frydoonfar HR, McGrath DR, Spigelman AD. Inhibition of proliferation of a colon cancer cell line by indole-3-carbinol. Colorectal Dis 2002; 4: 205-7.
102. Frydoonfar HR, McGrath DR, Spigelman AD. The effect of indole- 3-carbinol and sulforaphane on a prostate cancer cell line. ANZ J Surg 2003; 73: 154-6.
103. Suzui M, Inamine M, Kaneshiro T, et al. Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. Int J Oncol 2005; 27: 1391-9.
104. Salomons GS, Brady HJ, Verwijs-Janssen M, et al. The Bax alpha:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. Int J Cancer 1997; 71: 959-65.
105. Moiseeva EP, Fox LH, Howells LM, Temple LA, Manson MM. Indole-3-carbinol-induced death in cancer cells involves EGFR downregulation and is exacerbated in a 3D environment. Apoptosis 2006; 11: 799-812.
106. Kim DS, Jeong YM, Moon SI, et al. Indole-3-carbinol enhances ultraviolet B-induced apoptosis by sensitizing human melanoma cells. Cell Mol Life Sci 2006; 63: 2661-8.
107. Souli E, Machluf M, Morgenstern A, Sabo E, Yannai S. Indole-3- carbinol (I3C) exhibits inhibitory and preventive effects on prostate tumors in mice. Food Chem Toxicol 2008; 46: 863-70.
108. Kunimasa K, Kobayashi T, Sugiyama S, Kaji K, Ohta T. Indole-3- carbinol suppresses tumor-induced angiogenesis by inhibiting tube formation and inducing apoptosis. Biosci Biotechnol Biochem 2008; 72: 2243-6.
109. Banerjee S, Wang Z, Kong D, Sarkar FH. 3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res 2009; 69: 5592-600.
110. McGuire KP, Ngoubilly N, Neavyn M, Lanza-Jacoby S. 3,3'- diindolylmethane and paclitaxel act synergistically to promote apoptosis in HER2/Neu human breast cancer cells. J Surg Res 2006; 132: 208-13.
111. Ali S, Banerjee S, Ahmad A, El-Rayes BF, Philip PA, Sarkar FH. Apoptosis-inducing effect of erlotinib is potentiated by 3,3'- diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol Cancer Ther 2008; 7: 1708-19.
112. Abdelrahim M, Newman K, Vanderlaag K, Samudio I, Safe S. 3,3'- diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress- dependent upregulation of DR5. Carcinogenesis 2006; 27: 717-28.
113. Ge X, Fares FA, Yannai S. Induction of apoptosis in MCF-7 cells by indole-3-carbinol is independent of p53 and bax. Anticancer Res 1999; 19: 3199-203.
114. Chen DZ, Qi M, Auborn KJ, Carter TH. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr 2001; 131: 3294-302.
115. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann N Y Acad Sci 1999; 889: 204-13.
116. Le HT, Schaldach CM, Firestone GL, Bjeldanes LF. Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem 2003; 278: 21136-45.
117. Nachshon-Kedmi M, Fares FA, Yannai S. Therapeutic activity of 3,3'-diindolylmethane on prostate cancer in an in vivo model. Prostate 2004; 61: 153-60.
118. Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. J Nutr 2004; 134: 3493S-8S.
119. Li Y, Wang Z, Kong D, et al. Regulation of FOXO3a/beta- catenin/GSK-3beta signaling by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in prostate cancer cells. J Biol Chem 2007; 282: 21542-50.
120. Bhuiyan MM, Li Y, Banerjee S, et al. Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells. Cancer Res 2006; 66: 10064-72.
121. Khwaja FS, Wynne S, Posey I, Djakiew D. 3,3'-diindolylmethane induction of p75NTR-dependent cell death via the p38 mitogen- activated protein kinase pathway in prostate cancer cells. Cancer Prev Res (Phila Pa) 2009; 2: 566-71.
122. Ali S, Varghese L, Pereira L, et al. Sensitization of squamous cell carcinoma to cisplatin induced killing by natural agents. Cancer Lett 2009; 278: 201-9.
123. Chen Y, Xu J, Jhala N, et al. Fas-mediated apoptosis in cholangiocarcinoma cells is enhanced by 3,3'-diindolylmethane through inhibition of AKT signaling and FLICE-like inhibitory protein. Am J Pathol 2006; 169: 1833-42.
124. Pappa G, Lichtenberg M, Iori R, Barillari J, Bartsch H, Gerhauser C. Comparison of growth inhibition profiles and mechanisms of apoptosis induction in human colon cancer cell lines by isothiocyanates and indoles from Brassicaceae. Mutat Res 2006; 599: 76-87.
125. Kim EJ, Park SY, Shin HK, Kwon DY, Surh YJ, Park JH. Activation of caspase-8 contributes to 3,3'-Diindolylmethane- induced apoptosis in colon cancer cells. J Nutr 2007; 137: 31-6.
126. Savino JA, III, Evans JF, Rabinowitz D, Auborn KJ, Carter TH. Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane. Mol Cancer Ther 2006; 5: 556-63.
127. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5: 749-59.
128. Karin M. The IkappaB kinase - a bridge between inflammation and cancer. Cell Res 2008; 18: 334-42.
129. Ahmad A, Banerjee S, Wang Z, Kong D, Majumdar APN, Sarkar FH. Aging and Inflammation: Etiological culprits of Cancer. Current Aging Science 2009; 2: 174-86.
130. Wu K, Bonavida B. The activated NF-kappaB-Snail-RKIP circuitry in cancer regulates both the metastatic cascade and resistance to apoptosis by cytotoxic drugs. Crit Rev Immunol 2009; 29: 241-54.
131. Shen HM, Tergaonkar V. NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis 2009; 14: 348-63.
132. Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 2009; 8: 33-40.
133. Sarkar FH, Li Y, Wang Z, Kong D. NF-kappaB signaling pathway and its therapeutic implications in human diseases. Int Rev Immunol 2008; 27: 293-319.
134. Kim YS, Milner JA. Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem 2005; 16: 65-73.
135. Rahman KM, Sarkar FH. Steroid hormone mimics: molecular mechanisms of cell growth and apoptosis in normal and malignant mammary epithelial cells. J Steroid Biochem Mol Biol 2002; 80: 191-201.
136. Li Y, Chinni SR, Sarkar FH. Selective growth regulatory and pro- apoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells. Front Biosci 2005; 10: 236-43.
137. Takada Y, Andreeff M, Aggarwal BB. 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 2005; 106: 641-9.
138. Li Y, Sarkar FH. Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res 2002; 8: 2369-77.
139. Chinni SR, Sarkar FH. Akt inactivation is a key event in indole-3- carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 2002; 8: 1228-36.
140. Moiseeva EP, Heukers R. Indole-3-carbinol-induced modulation of NF-kappaB signalling is breast cancer cell-specific and does not correlate with cell death. Breast Cancer Res Treat 2008; 109: 451-62.
141. Rahman KM, Ali S, Aboukameel A, et al. Inactivation of NF- kappaB by 3,3'-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol Cancer Ther 2007; 6: 2757-65.
142. Kong D, Li Y, Wang Z, Banerjee S, Sarkar FH. Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res 2007; 67: 3310-9.
143. acour-Larose M, Hoang TM, Molla A. [Survivin, the starlet of the passenger-protein complex: check-up for its tenth anniversary]. Med Sci (Paris) 2008; 24: 828-32.
144. Romagnoli M, Seveno C, Bataille R, Barille-Nion S. [Survivin in cancerology: molecular aspects and therapeutic applications]. Med Sci (Paris) 2008; 24: 821-7.
145. Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res 2008; 14: 5000-5.
146. Altieri DC. Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 2008; 8: 61-70.
147. Yamamoto H, Ngan CY, Monden M. Cancer cells survive with survivin. Cancer Sci 2008; 99: 1709-14.
148. Andersen MH, Svane IM, Becker JC, Straten PT. The universal character of the tumor-associated antigen survivin. Clin Cancer Res 2007; 13: 5991-4.
149. Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy: fulfilled promises and open questions. Carcinogenesis 2007; 28: 1133-9.
150. Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy. Expert Opin Ther Targets 2008; 12: 463-76.
151. Rahman KM, Banerjee S, Ali S, et al. 3,3'-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. Cancer Res 2009; 69: 4468-75.
152. Kong D, Banerjee S, Huang W, et al. Mammalian target of rapamycin repression by 3,3'-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D- overexpressing PC3 cells. Cancer Res 2008; 68: 1927-34.
153. Ahmad A, Kong D, Sarkar SH, Wang Z, Banerjee S, Sarkar FH. Inactivation of uPA and its receptor uPAR by 3,3'- diindolylmethane (DIM) leads to the inhibition of prostate cancer cell growth and migration. J Cell Biochem 2009; 107: 516-27.
154. Bhatnagar N, Li X, Chen Y, Zhou X, Garrett SH, Guo B. 3,3'- diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin. Cancer Prev Res (Phila Pa) 2009; 2: 581-9.
155. Sreevalsan S, Jutooru I, Chadalapaka G, Walker M, Safe S. 1,1- Bis(3'-indolyl)-1-(p-bromophenyl)methane and related compounds repress survivin and decrease gamma-radiation-induced survivin in colon and pancreatic cancer cells. Int J Oncol 2009; 35: 1191-9.
156. Rao JS. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 2003; 3: 489-501.
157. Dass K, Ahmad A, Azmi AS, Sarkar SH, Sarkar FH. Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 2008; 34: 122-36.
158. Ahmad A, Kong D, Wang Z, Sarkar SH, Banerjee S, Sarkar FH. Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells. J Cell Biochem 2009; 108: 916-25.
159. Bradlow HL, Michnovicz J, Telang NT, Osborne MP. Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis 1991; 12: 1571-4.
160. Wattenberg LW, Loub WD. Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res 1978; 38: 1410-3.
161. Guo D, Schut HA, Davis CD, Snyderwine EG, Bailey GS, Dashwood RH. Protection by chlorophyllin and indole-3-carbinol against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)- induced DNA adducts and colonic aberrant crypts in the F344 rat. Carcinogenesis 1995; 16: 2931-7.
162. Wargovich MJ, Chen CD, Jimenez A, et al. Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreven- tive agents in the rat. Cancer Epidemiol Biomarkers Prev 1996; 5: 355-60.
163. Morse MA, LaGreca SD, Amin SG, Chung FL. Effects of indole-3- carbinol on lung tumorigenesis and DNA methylation induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and on the metabolism and disposition of NNK in A/J mice. Cancer Res 1990; 50: 2613-7.
164. Dashwood RH. Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables? Chem Biol Interact 1998; 110: 1-5.
165. Fong AT, Hendricks JD, Dashwood RH, Van WS, Lee BC, Bailey GS. Modulation of diethylnitrosamine-induced hepatocarcinoge- nesis and O6-ethylguanine formation in rainbow trout by indole-3- carbinol, beta-naphthoflavone, and Aroclor 1254. Toxicol Appl Pharmacol 1988; 96: 93-100.
166. Nixon JE, Hendricks JD, Pawlowski NE, Pereira CB, Sinnhuber RO, Bailey GS. Inhibition of aflatoxin B1 carcinogenesis in rainbow trout by flavone and indole compounds. Carcinogenesis 1984; 5: 615-9.
167. Newfield L, Goldsmith A, Bradlow HL, Auborn K. Estrogen metabolism and human papillomavirus-induced tumors of the larynx: chemo-prophylaxis with indole-3-carbinol. Anticancer Res 1993; 13: 337-41.
168. Rahman KM, Sarkar FH, Banerjee S, et al. Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model. Mol Cancer Ther 2006; 5: 2747-56.
169. Chang X, Tou JC, Hong C, et al. 3,3'-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis 2005; 26: 771-8.
170. Kassie F, Anderson LB, Scherber R, et al. Indole-3-carbinol inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo(a)pyrene-induced lung tumorigenesis in A/J mice and modulates carcinogen-induced alterations in protein levels. Cancer Res 2007; 67: 6502-11.
171. Kassie F, Matise I, Negia M, Upadhyaya P, Hecht SS. Dose- dependent inhibition of tobacco smoke carcinogen-induced lung tumorigenesis in A/J mice by indole-3-carbinol. Cancer Prev Res (Phila Pa) 2008; 1: 568-76.
172. Malejka-Giganti D, Parkin DR, Bennett KK, et al. Suppression of mammary gland carcinogenesis by post-initiation treatment of rats with tamoxifen or indole-3-carbinol or their combination. Eur J Cancer Prev 2007; 16: 130-41.
173. Kang JS, Kim DJ, Ahn B, et al. Post-initiation treatment of Indole- 3-carbinol did not suppress N-methyl-N-nitrosourea induced mammary carcinogenesis in rats. Cancer Lett 2001; 169: 147-54.
174. Shimano N, Uehara N, Kiyozuka Y, Shikata N, Tsubura A. Effects of prepubertal indole-3-carbinol treatment on development of N- methyl-N-nitrosourea-induced mammary carcinomas in female Sprague-Dawley rats. In vivo 2007; 21: 983-8.
175. Malejka-Giganti D, Niehans GA, Reichert MA, Bliss RL. Post- initiation treatment of rats with indole-3-carbinol or beta- naphthoflavone does not suppress 7, 12-dimethylbenz[a]anthra- cene-induced mammary gland carcinogenesis. Cancer Lett 2000; 160: 209-18.
176. Stoner G, Casto B, Ralston S, Roebuck B, Pereira C, Bailey G. Development of a multi-organ rat model for evaluating chemopre- ventive agents: efficacy of indole-3-carbinol. Carcinogenesis 2002; 23: 265-72.
177. Bradlow HL, Fishman J, Telang NT, Osborne MP. Re: Estrogen metabolism and excretion in Oriental and Caucasian women. J Natl Cancer Inst 1994; 86: 1643-5.
178. Bradlow HL, Michnovicz JJ, Halper M, Miller DG, Wong GY, Osborne MP. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev 1994; 3: 591-5.
179. McAlindon TE, Gulin J, Chen T, Klug T, Lahita R, Nuite M. Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. Lupus 2001; 10: 779-83.
180. Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord 1998; 22: 227-9.
181. Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst 1997; 89: 718-23.
182. Coll DA, Rosen CA, Auborn K, Potsic WP, Bradlow HL. Treatment of recurrent respiratory papillomatosis with indole-3- carbinol. Am J Otolaryngol 1997; 18: 283-5.
183. Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow HL. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1998; 118: 810-5.
184. Rosen CA, Bryson PC. Indole-3-carbinol for recurrent respiratory papillomatosis: long-term results. J Voice 2004; 18: 248-53.
185. Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo- controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 2000; 78: 123-9.
186. Reed GA, Peterson KS, Smith HJ, et al. A phase I study of indole- 3-carbinol in women: tolerability and effects. Cancer Epidemiol Biomarkers Prev 2005; 14: 1953-60.
187. Zeligs MA, Brownstone PK, Sharp ME, Westerlind K, Wilsom SM, Johs S. Managing cyclical mastalgia with absorbable diindolylmethane: A randomized, placebo-controlled trial. J Am Nutr Assoc 2005; 7: 5-14.
188. Sasieni P. Chemoprevention of cervical cancer. Best Pract Res Clin Obstet Gynaecol 2006; 20: 295-305.
189. Reed GA, Arneson DW, Putnam WC, et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3'-diindolylmethane. Cancer Epidemiol Biomarkers Prev 2006; 15: 2477-81.
190. Auborn KJ. Therapy for recurrent respiratory papillomatosis. Antivir Ther 2002; 7: 1-9.
191. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer 2004; 50: 161-7.
192. Reed GA, Sunega JM, Sullivan DK, et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3'- diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev 2008; 17: 2619-24.
193. Heath EI, Heilbrun LK, Vaishampayan UN, et al. A phase I dose- escalation study of oral BR-DIM (BioResponse 3,3'- Diindolylmethane) in castrate-resistant, non-metastatic, PSA relapse prostate cancer patients. 2009 Genitourinary Cancers Symposium, ASCO Abstract # 188. 2009.
194. Crowell JA, Page JG, Levine BS, Tomlinson MJ, Hebert CD. Indole-3-carbinol, but not its major digestive product 3,3'- diindolylmethane, induces reversible hepatocyte hypertrophy and cytochromes P450. Toxicol Appl Pharmacol 2006; 211: 115-23.
195. Leibelt DA, Hedstrom OR, Fischer KA, Pereira CB, Williams DE. Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 3,3'-diindolylmethane in sprague-dawley rats. Toxicol Sci 2003; 74: 10-21.
196. Anderton MJ, Manson MM, Verschoyle R, et al. Physiological modeling of formulated and crystalline 3,3'-diindolylmethane pharmacokinetics following oral administration in mice. Drug Metab Dispos 2004; 32: 632-8.
197. Katsman A, Umezawa K, Bonavida B. Chemosensitization and immunosensitization of resistant cancer cells to apoptosis and inhibition of metastasis by the specific NF-kappaB inhibitor DHMEQ. Curr Pharm Des 2009; 15: 792-808.
198. Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 2002; 1: 707-17.
199. Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2003; 2: 971-84.
200. Gewirtz DA. Growth arrest and cell death in the breast tumor cell in response to ionizing radiation and chemotherapeutic agents which induce DNA damage. Breast Cancer Res Treat 2000; 62: 223-35.
201. Haimsohn M, Beery R, Karasik A, Kanety H, Geier A. Aurintricarboxylic acid induces a distinct activation of the IGF-I receptor signaling within MDA-231 cells. Endocrinology 2002; 143: 837-45.
202. Nishikawa K, Satoh H, Hirai A, et al. alpha-Tocopheryloxybutyric acid enhances necrotic cell death in breast cancer cells treated with chemotherapy agent. Cancer Lett 2003; 201: 51-6.
203. Christensen JG, LeBlanc GA. Reversal of multidrug resistance in vivo by dietary administration of the phytochemical indole-3- carbinol. Cancer Res 1996; 56: 574-81.
204. Li Y, Ellis KL, Ali S, et al. Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line. Pancreas 2004; 28: e90-e95.
205. Arlt A, Gehrz A, Muerkoster S, et al. Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 2003; 22: 3243-51.
206. Chao WR, Yean D, Amin K, Green C, Jong L. Computer-aided rational drug design: a novel agent (SR13668) designed to mimic the unique anticancer mechanisms of dietary indole-3-carbinol to block Akt signaling. J Med Chem 2007; 50: 3412-5.
207. [207] Kapetanovic IM, Muzzio M, Hu SC, et al. Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys. Cancer Chemother Pharmacol 2009; epub ahead.
208. Safe S, Papineni S, Chintharlapalli S. Cancer chemotherapy with indole-3-carbinol, bis(3'-indolyl)methane and synthetic analogs. Cancer Lett 2008; 269: 326-38.
209. Weng JR, Tsai CH, Omar HA, et al. OSU-A9, a potent indole-3- carbinol derivative, suppresses breast tumor growth by targeting the Akt-NF-kappaB pathway and stress response signaling. Carcinogenesis 2009; 30: 1702-9.
210. Stephensen PU, Bonnesen C, Schaldach C, Andersen O, Bjeldanes LF, Vang O. N-methoxyindole-3-carbinol is a more efficient inducer of cytochrome P-450 1A1 in cultured cells than indol-3- carbinol. Nutr Cancer 2000; 36: 112-21.
211. McDougal A, Sethi-Gupta M, Ramamoorthy K, Sun G, Safe SH. Inhibition of carcinogen-induced rat mammary tumor growth and other estrogen-dependent responses by symmetrical dihalo- substituted analogs of diindolylmethane. Cancer Lett 2000; 151: 169-79.
212. McDougal A, Gupta MS, Morrow D, Ramamoorthy K, Lee JE, Safe SH. Methyl-substituted diindolylmethanes as inhibitors of estrogen-induced growth of T47D cells and mammary tumors in rats. Breast Cancer Res Treat 2001; 66: 147-57.
213. Vanderlaag K, Samudio I, Burghardt R, Barhoumi R, Safe S. Inhibition of breast cancer cell growth and induction of cell death by 1,1-bis(3'-indolyl)methane (DIM) and 5,5'-dibromoDIM. Cancer Lett 2006; 236: 198-212.
214. Lei P, Abdelrahim M, Cho SD, Liu X, Safe S. Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3'-indoly)-1-(p-substituted phenyl) methanes. Mol Cancer Ther 2008; 7: 3363-72.
215. Choi KH, Kim HK, Kim JH, et al. The p38 MAPK pathway is critical for 5,5'-dibromodiindolylmethane-induced apoptosis to prevent oral squamous carcinoma cells. Eur J Cancer Prev 2010; 19:153-9.
216. Ichite N, Chougule MB, Jackson T, Fulzele SV, Safe S, Singh M. Enhancement of docetaxel anticancer activity by a novel diindolylmethane compound in human non-small cell lung cancer. Clin Cancer Res 2009; 15: 543-52.
217. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442-54.
218. Sabbah M, Emami S, Redeuilh G, et al. Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat 2008; 11: 123-51.
219. Li Y, VandenBoom TG, Kong D, et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to- mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 2009; 69: 6704-12.
220. Ruvkun G. The perfect storm of tiny RNAs. Nat Med 2008; 14: 1041-5.
221. Melkamu T, Zhang X, Tan J, Zeng Y, Kassie F. Alteration of microRNA expression in vinyl-carbamate-induced mouse lung tumors and modulation by the chemopreventive agent indole-3- carbinol. Carcinogenesis 2010; 31(2): 252-8.