Targeted regulation of Pi3K/Akt/mTOR/NF-κB signaling by indole compounds and their derivatives: Mechanistic details and biological implications for cancer therapy

Anti-Cancer Agents in Medicinal Chemistry

Volumn 13, Issue 7, 2013, Pages 1002-1013

  Ahmad, Aamir ^a   Biersack, Bernhard ^b   Li, Yiwei ^a   Kong, Dejuan ^a   Bao, Bin ^a   Schobert, Rainer ^b   Padhye, Subhash B ^c   Sarkar, Fazlul H ^a  

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

^b UNIVERSITY OF BAYREUTH   (Germany)

^c ISTRA   (India)

Author keywords

Cancer therapy; Glucosinolates; Indole compounds; NF b; PI3K

Indexed keywords

2,3 DIINDOLYL TETRAMER; 3 CHLOROACETYLINDOLE; 3 INDOLEMETHANOL; 3, 3' DIINDOLYLMETHANE; 5 METHOXYINDOLE; 7 NITROINDOLE; ENZASTAURIN; EPIDERMAL GROWTH FACTOR; GENISTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDOLE DERIVATIVE; MAMMALIAN TARGET OF RAPAMYCIN; MICRORNA; OSU A 9; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; SILIBININ; SUNITINIB; UNCLASSIFIED DRUG; VINBLASTINE; VINCRISTINE;

ANGIOGENESIS; APOPTOSIS; ARTICLE; AUTOPHAGY; BREAST CANCER; CANCER THERAPY; CELL CYCLE PROGRESSION; CELL GROWTH; CELL INVASION; CELL METABOLISM; CELL SURVIVAL; COMPUTER AIDED DESIGN; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; LIVER CELL CARCINOMA; LUNG ADENOCARCINOMA; MOLECULAR INTERACTION; NONHUMAN;

ANIMALS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; HUMANS; INDOLES; MOLECULAR TARGETED THERAPY; NEOPLASMS; NF-KAPPA B; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84882803799     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/18715206113139990078     Document Type: Article

References (124)

1. Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin., 2012, 62, 10-29.
2. Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. Cellular signaling perturbation by natural products. Cell Signal, 2009, 21, 1541-1547.
3. Lee MM.; Gomez, S.L.; Chang, J.S.; Wey, M.; Wang, R.T.; Hsing, A.W. Soy and isoflavone consumption in relation to prostate cancer risk in China. Cancer Epidemiol. Biomarkers Prev., 2003, 12, 665-668.
4. Sarkar, F.H.; Li, Y. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics. Cancer Treat. Rev., 2009, 35, 597-607.
5. Ahmad, A.; Sakr, W.A.; Rahman, K.M. Anticancer properties of indole compounds: mechanism of apoptosis induction and role in chemotherapy. Curr. Drug Targets, 2010, 11, 652-666.
6. Kim, Y.S.; Milner, J.A. Targets for indole-3-carbinol in cancer prevention. J. Nutr. Biochem., 2005, 16, 65-73.
7. Aggarwal, B.B.; Ichikawa, H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle, 2005, 4, 1201-1215.
8. Rogan, E.G. The natural chemopreventive compound indole-3- carbinol: state of the science. In Vivo, 2006, 20, 221-228.
9. Safe, S.; Papineni, S.; Chintharlapalli, S. Cancer chemotherapy with indole-3-carbinol, bis(3'-indolyl)methane and synthetic analogs. Cancer Lett., 2008, 269, 326-338.
10. Bradlow, H.L. Review. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In Vivo, 2008, 22, 441-445.
11. Acharya, A.; Das, I.; Singh, S.; Saha, T. Chemopreventive properties of indole-3-carbinol, diindolylmethane and other constituents of cardamom against carcinogenesis. Recent Pat. Food Nutr. Agric., 2010, 2, 166-177.
12. Sarkar, F.H.; Li, Y. Indole-3-carbinol and prostate cancer. J. Nutr. 2004, 134, 3493S-3498S.
13. Weng, J.R.; Tsai, C.H.; Kulp, S.K.; Chen, C.S. Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett., 2008, 262, 153-163.
14. Ahmad, A.; Sakr, W.A.; Rahman, K.M.W. Role of Nuclear Factorkappa B Signaling in Anticancer Properties of Indole Compounds. J.Exp. Clin.Med., 2011, 3, 55-62.
15. Steinmetz, K.A.; Potter, J.D. Vegetables, fruit, and cancer prevention: a review. J. Am. Diet. Assoc., 1996;96:1027-39.
16. Michaud, D.S.; Spiegelman, D.; Clinton, S.K.; Rimm, E.B.; Willett, W.C.; Giovannucci, E.L. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J. Natl. Cancer Inst., 1999, 91, 605-613.
17. Johnson, I.S.; Armstrong, J.G.; Gorman, M.; Burnett, J.P. Jr. The Vinca alkaloids: a new class of oncolytic agents. Cancer Res., 1963, 23, 1390-1427.
18. Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchya, H.; Takahashi, Y.; Masuma, R. A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J. Antibiot. (Tokyo), 1977, 30, 275-282.
19. Barrios, C.H.; Liu, M.C.; Lee, S.C.; Vanlemmens, L.; Ferrero, J.M.; Tabei, T.; Pivot, X.; Iwata, H.; Aogi, K.; Lugo-Quintana, R.; Harbeck, N.; Brickman, M.J.; Zhang, K.; Kern, K.A.; Martin, M. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res. Treat, 2010, 121, 121-131.
20. Mina, L.; Krop, I.; Zon, R.T.; Isakoff, S.J.; Schneider, C.J.; Yu, M.; Johnson, C.; Vaughn, L.G.; Wang, Y.; Hristova-Kazmierski, M.; Shonukan, O.O.; Sledge, G.W.; Miller, K.D. A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen. Invest. New Drug., 2009, 27(6):565-570
21. Oganesian, A.; Hendricks, J.D.; Williams, D.E. Long term dietary indole-3-carbinol inhibits diethylnitrosamine-initiated hepatocarcinogenesis in the infant mouse model. Cancer Lett., 1997, 118, 87-94.
22. Jin, L.; Qi, M.; Chen, D.Z.; Anderson, A.; Yang, G.Y.; Arbeit, J.M.; Auborn, K.J. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res., 1999, 59, 3991-3997.
23. He, Y.H.; Friesen, M.D.; Ruch, R.J.; Schut, H.A. 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.
24. Kojima, T.; Tanaka, T.; Mori, H. Chemoprevention of spontaneous endometrial cancer in female Donryu rats by dietary indole-3- carbinol. Cancer Res., 1994, 54, 1446-1449.
25. Wong, G.Y.; Bradlow, L.; Sepkovic, D.; Mehl, S.; Mailman, J.; Osborne, M.P. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J. Cell Biochem. Suppl., 1997, 28-29, 111-116.
26. Yuan, F.; Chen, D.Z.; Liu, K.; Sepkovic, D.W.; Bradlow, H.L.; Auborn, K. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res., 1999, 19, 1673-1680.
27. Verhoeven, D.T.; Verhagen, H.; Goldbohm, R.A.; van den Brandt, P.A.; van, P.G. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem. Biol. Interact., 1997, 103, 79-129.
28. Holst, B.; Williamson, G. A critical review of the bioavailability of glucosinolates and related compounds. Nat. Prod. Rep., 2004, 21, 425-447.
29. McDanell, R.; McLean, A.E.; Hanley, A.B.; Heaney, R.K.; Fenwick, G.R. 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, 289-293.
30. Terry, P.; Wolk, A.; Persson, I.; Magnusson, C. Brassica vegetables and breast cancer risk. JAMA, 2001, 285, 2975-2977.
31. van, P.G.; Verhoeven, D.T.; Verhagen, H.; Goldbohm, R.A. Brassica vegetables and cancer prevention. Epidemiology and mechanisms. Adv. Exp. Med. Biol., 1999, 472, 159-168.
32. Verhagen, H.; Poulsen, H.E.; Loft, S.; van Poppel, G.; Willems, M.I.; van Bladeren, P.J. Reduction of oxidative DNA-damage in humans by brussels sprouts. Carcinogenesis, 1995, 16, 969-970.
33. Keck, A.S.; Finley, J.W. Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Integr. Cancer Ther., 2004, 3, 5-12.
34. Grubbs, C.J.; Steele, V.E.; Casebolt, T.; Juliana, M.M.; Eto, I.; Whitaker, L.M.; Dragnev, K.H.; Kelloff, G.J.; Lubet, R.L. Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res., 1995, 15, 709-716.
35. Shertzer, H.G.; Senft, A.P. The micronutrient indole-3-carbinol: implications for disease and chemoprevention. Drug Metabol. Drug Interact., 2000, 17, 159-188.
36. Dashwood, R.H.; Fong, A.T.; Arbogast, D.N.; Bjeldanes, L.F.; Hendricks, J.D.; Bailey, G.S. Anticarcinogenic activity of indole-3- carbinol acid products: ultrasensitive bioassay by trout embryo microinjection. Cancer Res., 1994, 54, 3617-3619.
37. Shaw, R.J.; Cantley, L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 2006, 441, 424-430.
38. Luo, J.; Manning, B.D.; Cantley, L.C. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell, 2003, 4, 257-262.
39. Manning, B.D.; Cantley, L.C. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem. Soc. Trans., 2003, 31, 573-578.
40. Hay, N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell, 2005, 8, 179-183.
41. LoPiccolo, J.; Blumenthal, G.M.; Bernstein, W.B.; Dennis, P.A. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist. Updat., 2008, 11, 32-50.
42. Falasca, M.; Selvaggi, F.; Buus, R.; Sulpizio, S.; Edling, C.E. Targeting phosphoinositide 3-kinase pathways in pancreatic cancer--from molecular signalling to clinical trials. Anticancer Agents Med. Chem., 2011, 11, 455-463.
43. Nahta, R.; O'Regan, R.M. Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/ mTOR pathway. Clin. Breast Cancer, 2010;10 Suppl 3, S72-S78.
44. Karin, M.; Cao, Y.; Greten, F.R.; Li, Z.W. NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer, 2002, 2, 301-310.
45. Karin, M. Nuclear factor-kappaB in cancer development and progression. Nature, 2006, 441, 431-436.
46. Lin, Y.; Bai, L.; Chen, W.; Xu, S. The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin. Ther. Targets, 2010, 14, 45-55.
47. Li, F.; Sethi, G. Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim. Biophys. Acta, 2010, 1805, 167-180.
48. Ahmad, A.; Banerjee, S.; Wang, Z.; Kong D.; Majumdar, A.P.; Sarkar, F.H. Aging and inflammation: etiological culprits of cancer. Curr. Aging Sci., 2009, 2, 174-186.
49. Luqman, S.; Pezzuto, J.M. NFkappaB: a promising target for natural products in cancer chemoprevention. Phytother. Res., 2010, 24, 949-963.
50. Staudt, L.M. Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect. Biol., 2010, 2, a000109.
51. Ozes, O.N.; Mayo, L.D.; Gustin, J.A.; Pfeffer, S.R.; Pfeffer, L.M.; Donner, D.B. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature, 1999, 401, 82-85.
52. Romashkova, J.A.; Makarov, S.S. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature, 1999, 401, 86-90.
53. Meng, F.; Liu, L.; Chin, P.C.; D'Mello, S.R. Akt is a downstream target of NF-kappa B. J. Biol. Chem., 2002, 277, 29674-29680.
54. Salminen, A.; Kaarniranta, K. Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell Signal, 2010, 22, 573-577.
55. Dan, H.C.; Cooper, M.J.; Cogswell, P.C.; Duncan, J.A.; Ting, J.P.; Baldwin, A.S. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev., 2008, 22, 1490-500.
56. Chinni, S.R.; Sarkar, F.H. Akt inactivation is a key event in indole- 3-carbinol-induced apoptosis in PC-3 cells. Clin. Cancer Res., 2002, 8, 1228-1236.
57. Rahman, K.M.; Li, Y.; Sarkar, F.H. Inactivation of akt and NFkappaB play important roles during indole-3-carbinol-induced apoptosis in breast cancer cells. Nutr. Cancer, 2004, 48, 84-94.
58. Kassie, F.; Kalscheuer, S.; Matise, I.; Ma, L.; Melkamu, T.; Upadhyaya, P.; Hecht, S.S. Inhibition of vinyl carbamate-induced pulmonary adenocarcinoma by indole-3-carbinol and myo-inositol in A/J mice. Carcinogenesis, 2010, 31, 239-245.
59. Kassie, F.; Melkamu, T.; Endalew, A.; Upadhyaya, P.; Luo, X.; Hecht, S.S. Inhibition of lung carcinogenesis and critical cancer-related signaling pathways by N-acetyl-S-(N-2- phenethylthiocarbamoyl)-l-cysteine, indole-3-carbinol and myoinositol, alone and in combination. Carcinogenesis, 2010, 31, 1634-1641.
60. Kassie, F.; Matise, I.; Negia, M.; Upadhyaya, P.; Hecht, S.S. Dosedependent inhibition of tobacco smoke carcinogen-induced lung tumorigenesis in A/J mice by indole-3-carbinol. Cancer Prev. Res. (Phila), 2008, 1, 568-576.
61. Dagne, A.; Melkamu, T.; Schutten, M.M.; Qian X, Upadhyaya P, Luo X, Kassie F. Enhanced inhibition of lung adenocarcinoma by combinatorial treatment with indole-3-carbinol and silibinin in A/J mice. Carcinogenesis, 2011, 32, 561-567.
62. Qian, X.; Melkamu, T.; Upadhyaya, P.; Kassie, F. Indole-3- carbinol inhibited tobacco smoke carcinogen-induced lung adenocarcinoma in A/J mice when administered during the postinitiation or progression phase of lung tumorigenesis. Cancer Lett., 2011, 311, 57-65.
63. Nakamura, Y.; Yogosawa, S.; Izutani, Y.; Watanabe, H.; Otsuji, E.; Sakai, T. A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol. Cancer, 2009, 8, 100.
64. Chao, W.R.; Yean, D.; Amin, K.; Green, C.; Jong, L. Computeraided 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, 3412-3415.
65. Weng JR, Bai LY, Omar HA, et al. A novel indole-3-carbinol derivative inhibits the growth of human oral squamous cell carcinoma in vitro. Oral Oncol., 2010, 46, 748-754.
66. De, S.M.; Galluzzi, L.; Lucarini, S.; Paoletti, M.F.; Fraternale, A.; Duranti, A.; De Marco, C.; Fanelli, M.; Zaffaroni, N.; Brandi, G.; Magnani, M. The indole-3-carbinol cyclic tetrameric derivative CTet inhibits cell proliferation via overexpression of p21/CDKN1A in both estrogen receptor-positive and triple-negative breast cancer cell lines. Breast Cancer Res., 2011, 13, R33.
67. Kim, D.J.; Reddy, K.; Kim, M.O.; Li, Y.; Nadas, J.; Cho, Y.Y.; Kim, J.E.; Shim, J.H.; Song, N.R.; Carper, A.; Lubet, R.A.; Bode, A.M.; Dong, Z. (3-Chloroacetyl)-indole, a novel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo. Cancer Prev. Res. (Phila), 2011, 4, 1842-1851.
68. Hwang JW, Jung JW, Lee YS, Kang KS. Indole-3-carbinol prevents H(2)O(2)-induced inhibition of gap junctional intercellular communication by inactivation of PKB/Akt. J. Vet. Med. Sci., 2008, 70, 1057-1063.
69. Li Y, Chinni SR, Sarkar FH. Selective growth regulatory and proapoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells. Front Biosci., 2005, 10, 236-243.
70. Rahman, K.W.; Sarkar, F.H. Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3, 3'-diindolylmethaneinduced apoptosis in breast cancer cells. Cancer Res., 2005, 65, 364-371.
71. Garikapaty, V.P.; Ashok, B.T.; Tadi, K.; Mittelman, A.; Tiwari, R.K. Synthetic dimer of indole-3-carbinol: second generation diet derived anti-cancer agent in hormone sensitive prostate cancer. Prostate, 2006, 66, 453-462.
72. Garikapaty, V.P.; Ashok, B.T.; Tadi, K.; Mittelman, A.; Tiwari, R.K. 3, 3'-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer. Biochem. Biophys. Res. Commun., 2006, 340, 718-725.
73. Bhuiyan, M.M.; 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, 66:10064-10072.
74. Wang, Z.; Yu, B.W.; Rahman, K.M.; Ahmad, F. Sarkar, F.H. 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, 341-349.
75. 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, 1927-1934.
76. Rajoria, S.; Suriano, R.; Wilson, Y.L., et al. 3, 3'-diindolylmethane inhibits migration and invasion of human cancer cells through combined suppression of ERK and AKT pathways. Oncol. Rep., 2011, 25, 491-497.
77. Guan, H.; Zhu, L.; Fu, M., et al. 3, 3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. PLoS One, 2012, 7, e34957.
78. 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, 1833-1842.
79. Gao, N.; Cheng, S., Budhraja, A., et al. 3, 3'-Diindolylmethane exhibits antileukemic activity in vitro and in vivo through a Aktdependent process. PLoS One, 2012, 7, e31783.
80. Zhu, J.; Li, Y.; Guan, C.; Chen, Z. Anti-proliferative and proapoptotic effects of 3, 3'-diindolylmethane in human cervical cancer cells. Oncol. Rep., 2012, 28, 1063-1068.
81. Weng, J.R.; Bai, L.Y.; Chiu, C.F.; Wang, Y.C.; Tsai, M.H. The dietary phytochemical 3, 3'-diindolylmethane induces G2/M arrest and apoptosis in oral squamous cell carcinoma by modulating Akt- NF-kappaB, MAPK, and p53 signaling. Chem. Biol. Interact., 2012, 195, 224-230.
82. Kunimasa, K.; Kobayashi, T.; Kaji, K.; Ohta, T. Antiangiogenic effects of indole-3-carbinol and 3, 3'-diindolylmethane are associated with their differential regulation of ERK1/2 and Akt in tube-forming HUVEC. J. Nutr., 2010, 140, 1-6.
83. Sarkar, F.H.; Li, Y. Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res., 2006, 66, 3347-3350.
84. Rahman, K.M.; Ali, S.; Aboukameel, A. et al. Inactivation of NFkappaB by 3, 3'-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol. Cancer Ther., 2007, 6, 2757-2765.
85. Ichite, N.; Chougule, M.; Patel, A.R. et al. Inhalation delivery of a novel diindolylmethane derivative for the treatment of lung cancer. Mol. Cancer Ther., 2010, 9, 3003-3014.
86. Banerjee, S.; Kong, D.; Wang, Z. et al. Attenuation of multitargeted proliferation-linked signaling by 3, 3'-diindolylmethane (DIM): from bench to clinic. Mutat. Res., 2011, 728, 47-66.
87. Gitto, R.; De, L.L.; Ferro, S. et al. Development of 3-substituted- 1H-indole derivatives as NR2B/NMDA receptor antagonists. Bioorg. Med. Chem., 2009, 17, 1640-1647.
88. Li, Q.; Li, T.; Zhu, G.D. et al. Discovery of trans-3, 4'- bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation. Bioorg. Med. Chem. Lett., 2006, 16, 1679-1685.
89. Zhu, G.D.; Gandhi, V.B.; Gong, J. et al. Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers. Bioorg. Med. Chem. Lett., 2006, 16, 3424-3429.
90. Guo, W.; Wu, S.; Liu, J.; Fang, B. Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota. Cancer Res., 2008, 68, 7403-7408.
91. Wu, S.; Wang, L.; Guo, W. et al. Analogues and derivatives of oncrasin-1, a novel inhibitor of the C-terminal domain of RNA polymerase II and their antitumor activities. J. Med. Chem., 2011, 54, 2668-2679.
92. Carbonnelle, D.; Duflos, M.; Marchand, P. et al. A novel indole-3- propanamide exerts its immunosuppressive activity by inhibiting JAK3 in T cells. J. Pharmacol. Exp. Ther., 2009, 331, 710-716.
93. Singh, R.K.; Lange, T.S.; Kim, K. et al. Effect of indole ethyl isothiocyanates on proliferation, apoptosis, and MAPK signaling in neuroblastoma cell lines. Bioorg. Med. Chem. Lett., 2007, 17, 5846-5852.
94. Singh, R.K.; Lange, T.S.; Kim, K.K. et al. Isothiocyanate NB7M causes selective cytotoxicity, pro-apoptotic signalling and cellcycle regression in ovarian cancer cells. Br. J. Cancer, 2008, 99, 1823-1831.
95. Brard, L.; Singh, R.K.; Kim, K.K.; Lange, T.S.; Sholler, G.L. Induction of cytotoxicity, apoptosis and cell cycle arrest by 1-tbutyl carbamoyl, 7-methyl-indole-3-ethyl isothiocyanate (NB7M) in nervous system cancer cells. Drug Des. Devel. Ther., 2009, 2, 61-69.
96. Weng, J.R.; Tsai, C.H.; Kulp, S.K. et al. A potent indole-3- carbinol derived antitumor agent with pleiotropic effects on multiple signaling pathways in prostate cancer cells. Cancer Res., 2007, 67, 7815-7824.
97. Weng, J.R.; Tsai, C.H.; Omar, H.A. 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, 1702-1709.
98. Omar, H.A.; Sargeant, A.M.; Weng, J.R. et al. Targeting of the Akt-nuclear factor-kappa B signaling network by [1-(4-chloro-3- nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), a novel indole-3-carbinol derivative, in a mouse model of hepatocellular carcinoma. Mol. Pharmacol., 2009, 76, 957-968.
99. Sarkaria, J.N.; Tibbetts, R.S.; Busby, E.C. et al. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res., 1998, 58, 4375-4382.
100. Ding, H.; Zhang, C.; Wu, X. et al. Novel indole alpha-methylenegamma- lactones as potent inhibitors for AKT-mTOR signaling pathway kinases. Bioorg. Med. Chem. Lett., 2005, 15, 4799-4802.
101. Zhang, C.; Yang, N.; Yang, C.H. et al. S9, a novel anticancer agent, exerts its anti-proliferative activity by interfering with both PI3K-Akt-mTOR signaling and microtubule cytoskeleton. PLoS One, 2009, 4, e4881.
102. Jobson, A.G.; Lountos, G.T.; Lorenzi, P.L. et al. Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)- ethyl]-phenyl}-amide]. J. Pharmacol. Exp. Ther., 2009, 331, 816-826.
103. Finlay, M.R.; Buttar, D.; Critchlow, S.E. et al. Sulfonylmorpholino- pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor. Bioorg. Med. Chem. Lett., 2012, 22, 4163-4168.
104. Viola, G.; Bortolozzi, R.; Hamel, E.; Moro, S.; Brun, P.; Castagliuolo, I.; Ferlin, M.G.; Basso, G. MG-2477, a new tubulin inhibitor, induces autophagy through inhibition of the Akt/mTOR pathway and delayed apoptosis in A549 cells. Biochem. Pharmacol., 2012, 83, 16-26.
105. Gasparotto, V.; Castagliuolo, I.; Ferlin, M.G. 3-substituted 7- phenyl-pyrroloquinolinones show potent cytotoxic activity in human cancer cell lines. J. Med. Chem., 2007, 50, 5509-5513.
106. Chintharlapalli, S.; Papineni, S.; Safe, S. 1, 1-Bis(3'-indolyl)-1-(psubstituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPARgamma-dependent and PPARgammaindependent pathways. Mol. Cancer Ther., 2006, 5, 1362-1370.
107. Takahashi, C.; Numata, A.; Ito, Y.; Matsumura, E.; Araki, H.; Iwaki, H.; Kushida, K. Leptosins, antitumour metabolites of a fungus isolated from a marine alga. J. Chem. Soc. Perkin Trans., 1994, 1, 1859-1864.
108. Yanagihara, M.; Sasaki-Takahashi, N.; Sugahara, T.; Yamamoto, S.; Shinomi, M.; Yamashita, I.; Hayashida, M.; Yamanoha, B.; Numata, A.; Yamori, T.; Andoh, T. Leptosins isolated from marine fungus Leptoshaeria species inhibit DNA topoisomerases I and/or II and induce apoptosis by inactivation of Akt/protein kinase B. Cancer Sci., 2005, 96, 816-824.
109. Karaman, M.W.; Herrgard, S.; Treiber, D.K.; Gallant, P.; Atteridge, C.E.; Campbell, B.T.; Chan, K.W.; Ciceri, P.; Davis, M.I.; Edeen, P.T.; Faraoni, R.; Floyd, M.; Hunt, J.P.; Lockhart, D.J.; Milanov, Z.V.; Morrison, M.J.; Pallares, G.; Patel, H.K.; Pritchard, S.; Wodicka, L.M.; Zarrinkar, P.P. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol., 2008, 26, 127-132.
110. Tevaarwerk, A.; Wilding, G.; Eickhoff, J.; Chappell, R.; Sidor, C.; Arnott, J.; Bailey, H.; Schelman, W.; Liu, G. Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design. Invest. New Drugs, 2012, 30, 1039-1045.
111. Dowling, J.E.; Chuaqui, C.; Pontz, T.W.; Lyne, P.D.; Larsen, N.A.; Block, M.H.; Chen, H.; Su, N.; Wu, A.; Russell, D.; Pollard, H.; Lee, J.W.; Peng, B.; Thakur, K.; Ye, Q.; Zhang, T.; Brassil, P.; Racicot, V.; Bao, L.; Denz, C.R.; Cooke, E. Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization. ACS Med. Chem. Lett., 2012, 3, 278-283.
112. Bursavich, M.G.; Brooijmans, N.; Feldberg, L.; Hollander, I.; Kim, S.; Lombardi, S.; Park, K.; Mallon, R.; Gilbert, A.M. Novel benzofuran-3-one indole inhibitors of PI3 kinase-alpha and the mammalian target of rapamycin: hit to lead studies. Bioorg. Med. Chem. Lett., 2010, 20, 2586-2590.
113. Zhang, N.; Ayral-Kaloustian, S.; Anderson, J.T.; Nguyen, T.; Das, S.; Venkatesan, A.M.; Brooijmans, N.; Lucas, J.; Yu, K.; Hollander, I.; Mallon, R. 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer. Bioorg. Med. Chem. Lett., 2010, 20, 3526-3529.
114. Iwatsuki, M.; Mimori, K.; Yokobori, T.; Ishi, H.; Beppu, T.; Nakamori, S.; Baba, H.; Mori, M. Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci., 2010, 101, 293-299.
115. Wang, Z.; Li, Y.; Ahmad, A.; Azmi, A.S.; Kong, D.; Banerjee, S.; Sarkar, F.H. Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist. Updat., 2010, 13, 109-118.
116. Ahmad, A.; Aboukameel, A.; Kong, D.; Wang, Z.; Sethi, S.; Chen, W.; Sarkar, F.H.; Raz, A. Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer Res., 2011, 71, 3400-3409.
117. Larue, L.; Bellacosa, A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene, 2005, 24, 7443-7454.
118. Lamouille, S.; Derynck, R. Emergence of the phosphoinositide 3- kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-beta-induced epithelial-mesenchymal transition. Cells Tissues Organs, 2011, 193, 8-22.
119. Kasinski, A.L.; Slack, F.J. Potential microRNA therapies targeting Ras, NFkappaB and p53 signaling. Curr. Opin. Mol. Ther., 2010, 12, 147-157.
120. Li, Y.; VandenBoom, T.G.; Kong, D.; Wang, Z.; Ali, S.; Philip, P.A.; Sarkar, F.H. 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, 6704-6712.
121. Ahmad, A.; Sarkar, SH; Bitar, B.; Ali, S.; Aboukameel, A.; Sethi, S.; Li, Y.; Bao, B.; Kong, D.; Banerjee, S.; Padhye, S.B.; Sarkar, F.H. Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo leading to anticancer activity against breast cancer cells. Mol. Cancer Ther., 2012.
122. Boldin, M.P.; Baltimore, D. MicroRNAs, new effectors and regulators of NF-kappaB. Immunol. Rev., 2012, 246, 205-220.
123. Ma, X.; Becker, Buscaglia, L.E.; Barker, J.R.; Li, Y. MicroRNAs in NF-kappaB signaling. J. Mol. Cell. Biol., 2011, 3, 159-166.
124. Li, Y.; Kong, D.; Ahmad, A.; Bao, B.; Sarkar, F.H. Targeting bone remodeling by isoflavone and 3, 3'-diindolylmethane in the context of prostate cancer bone metastasis. PLoS One, 2012, 7, e33011.