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1.  Induction of the Transcriptional Repressor ZBTB4 in Prostate Cancer Cells by Drug-induced Targeting of microRNA-17-92/106b-25 Clusters 
Molecular cancer therapeutics  2012;11(9):1852-1862.
Androgen-insensitive DU145 and PC3 human prostate cancer cells express high levels of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4, and treatment of cells with methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) inhibited cell growth and downregulated Sp1, Sp3 and Sp4 expression. CDODA-Me (15 mg/kg/d) was a potent inhibitor of tumor growth in a mouse xenograft model (PC3 cells) and also decreased expression of Sp transcription factors in tumors. CDODA-Me-mediated downregulation of Sp1, Sp3 and Sp4 was due to induction of the transcriptional repressor ZBTB4 which competitively binds and displaces Sp transcription factors from GC-rich sites in Sp1, Sp3, Sp4 and Sp-regulated gene promoters. ZBTB4 levels are relatively low in DU145 and PC3 cells due to suppression by microRNA (miR) paralogs that are members of the miR-17-92 (miR-20a/17-5p) and miR-106b-25 (miR-106b/93) clusters. Examination of publically available prostate cancer patient array data showed an inverse relationship between ZBTB4 and miRs-20a/17-5p/106b/93 expression, and increased ZBTB4 in prostate cancer patients was a prognostic factor for increased survival. CDODA-Me induces ZBTB4 in prostate cancer cells through disruption of miR-ZBTB4 interactions and this results in downregulation of pro-oncogenic Sp transcription factors and Sp-regulated genes.
doi:10.1158/1535-7163.MCT-12-0181
PMCID: PMC3632183  PMID: 22752225
ZBTB4; CDODA-Me; Sp; miR-17-92; miR-106b
2.  INHIBITION OF PITUITARY TUMOR-TRANSFORMING GENE-1 IN THYROID CANCER CELLS BY DRUGS THAT DECREASE SPECIFICITY PROTEINS 
Molecular carcinogenesis  2011;50(9):655-667.
Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) and the corresponding 2-trifluoromethyl analog (CF3DODA-Me) are derived synthetically from the triterpenoid glycyrrhetinic acid, a major component of licorice. CDODA-Me and CF3DODA-Me inhibited growth of highly invasive ARO, DRO, K-18 and HTh-74 thyroid cancer cells and this was due, in part, to decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 that are overexpressed in these cells. CDODA-Me and CF3DODA-Me also decreased expression of Sp-dependent genes, such as survivin and vascular endothelial growth factor, and induced apoptosis. In addition, pituitary tumor-transforming gene-1 (PTTG-1) protein and mRNA levels were also decreased in thyroid cancer cells treated with CDODA-Me or CF3DODA-Me and this was accompanied by decreased expression of PTTG-1-dependent c-Myc and fibroblast growth factor 2 genes. RNA interference studies against Sp1, Sp3 and Sp4 proteins showed that in thyroid cancer cells, PTTG-1 was an Sp-dependent gene. This study demonstrates for the first time that drugs, such as CDODA-Me and CF3DODA-Me, that decrease Sp protein expression also downregulate PTTG-1 in thyroid cancer cells and therefore have potential for clinical treatment of thyroid cancer and other endocrine neoplasias where PTTG-1 is a major pro-oncogenic factor.
doi:10.1002/mc.20738
PMCID: PMC3128656  PMID: 21268135
PTTG-1; Sp proteins; thyroid cancer; anticancer agents
3.  INACTIVATION OF THE ORPHAN NUCLEAR RECEPTOR TR3/Nur77 INHIBITS PANCREATIC CANCER CELL AND TUMOR GROWTH 
Cancer research  2010;70(17):6824-6836.
Activation of the orphan nuclear receptor TR3/Nur77 (NR4A1) promotes apoptosis and inhibits pancreatic tumor growth, but its endogenous function and the effects of its inactivation have yet to be determined. TR3 was overexpressed in human pancreatic tumors compared to non-tumor tissue. siRNA-mediated knockdown of TR3 or cell treatment with the TR3 antagonist 1, 1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) decreased proliferation, induced apoptosis, and decreased expression of anti-apoptotic genes including Bcl-2 and survivin in pancreatic cancer cells. Survivin suppression was mediated by formation of a TR3-Sp1-p300 DNA binding complex on the proximal GC-rich region of the survivin promoter. When administered in vivo DIM-C-pPhOH induced apoptosis and inhibited tumor growth in an orthotopic model of pancreatic cancer, associated with inhibition of the same anti-apoptotic markers observed in vitro. Our results offer preclinical validation of TR3 as a drug target for pancreatic cancer chemotherapy, based on the ability of TR3 inhibitors to block the growth of pancreatic tumors.
doi:10.1158/0008-5472.CAN-10-1992
PMCID: PMC2988472  PMID: 20660371
TR3; Nur77; drug target; pancreatic cancer
4.  Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors 
BMC Cancer  2011;11:371.
Background
Betulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells.
Methods
The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression.
Results
BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10.
Conclusions
These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent.
doi:10.1186/1471-2407-11-371
PMCID: PMC3170653  PMID: 21864401
5.  Peroxisome Proliferator-Activated Receptor γ-Dependent Activity of Indole Ring-Substituted 1,1-Bis(3'-indolyl)-1-(p-biphenyl)methanes in Cancer Cells 
1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) substituted in the phenyl ring with a para-, t-butyl, trifluoro or phenyl (DIM-C-pPhC6H5) group activates peroxisome proliferator-activated receptor γ (PPARγ) in several cancer cell lines. In this study, we have examined the effects of 5,5'-dihyroxy, 5,5'-dimethyl, 5,5'-dibromo, 5,5'-dinitro and 5,5'-dimethoxyindole ring substituted analogs of DIM-C-pPhC6H5 on their activity as PPARγ agonists. Introduction of the 5,5'-dihydroxy and 5,5'-dimethyl substituents enhanced activation of PPARγ in colon and pancreatic cancer cells. However, activation of p21 in Panc28 pancreatic cancer cells and induction of caveolin-1 and KLF4 in colon cancer cells by the cells by these C-DIMs was structure- and cell context-dependent. The results demonstrate that DIM-C-pPhC6H5 and indole ring-substituted analogs are selective PPARγ modulators.
doi:10.1007/s00280-009-1144-0
PMCID: PMC2854866  PMID: 19823826
C-DIMs; PPARγ agonists; indole ring substituents
6.  Oncogenic MicroRNA-27a Is A Target For Anticancer Agent Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate in Colon Cancer Cells 
Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic derivative of glycyrrhetinic acid, a triterpenoid phytochemical found in licorice extracts. CDODA-Me inhibited growth of RKO and SW480 colon cancer cells and this was accompanied by decreased expression of Sp1, Sp3 and Sp4 protein and mRNA and several Sp-dependent genes including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1 or Flt-1). CDODA-Me also induced apoptosis, arrested RKO and SW480 cells at G2/M, and inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. CDODA-Me decreased expression of microRNA-27a (miR-27a), and this was accompanied by increased expression of two miR-27a-regulated mRNAs, namely ZBTB10 (an Sp repressor) and Myt-1 which catalyzes phosphorylation of cdc2 to inhibit progression of cells through G2/M. Both CDODA-Me and antisense miR-27a induced comparable responses in RKO and SW480 cells, suggesting that the potent anticarcinogenic activity of CDODA-Me is due to repression of oncogenic miR-27a.
doi:10.1002/ijc.24530
PMCID: PMC2766353  PMID: 19582879
CDODA-Me; anticarcinogenicity; miR-27a; colon cancer; cell cycle
7.  Induction of Apoptosis and Nonsteroidal Antiinflammatory Drug-Activated Gene 1 in Pancreatic Cancer Cells By A Glycyrrhetinic Acid Derivative 
Molecular carcinogenesis  2009;48(8):692-702.
Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic triterpenoid derived from glycyrrhetinic acid, a bioactive phytochemical in licorice, CDODA-Me inhibits growth of Panc1 and Panc28 pancreatic cancer cell lines and activates peroxisome proliferator-activated receptor γ (PPARγ)-dependent transactivation in these cells. CDODA-Me also induced p21 and p27 protein expression and downregulates cyclin D1; however, these responses were receptor-independent. CDODA-Me induced apoptosis in Panc1 and Panc28 cells, and this was accompanied by receptor-independent induction of the proapoptotic proteins early growth response-1 (Egr-1), nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), and activating transcription factor-3 (ATF3). Induction of NAG-1 and Egr-1 by CDODA-Me was dependent on activation of phosphatidylinositol-3-kinase (PI3-K) and/or p42 and p38 mitogen-activated protein kinase (MAPK) pathways but there were differences between Panc28 and Panc1 cells. Induction of NAG-1 in Panc28 cells was p38-MAPK- and PI3-K-dependent but Egr-1-independent, whereas induction in Panc1 cells was associated with activation of p38-MAPK, PI3-K and p42-MAPK and was only partially Egr-1-dependent. This is the first report of the induction of the proapoptotic protein NAG-1 in pancreatic cancer cells.
doi:10.1002/mc.20518
PMCID: PMC2746008  PMID: 19125423
CDODA-Me; pancreatic cancer; apoptosis
8.  Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met 
Carcinogenesis  2009;30(7):1193-1201.
The non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 μM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.
doi:10.1093/carcin/bgp092
PMCID: PMC2704282  PMID: 19406933
9.  p21 EXPRESSION IS INDUCED BY ACTIVATION OF NUCLEAR NERVE GROWTH FACTOR-INDUCED Bα (NGFI-Bα, NUR77) IN PANCREATIC CANCER CELLS 
Molecular cancer research : MCR  2009;7(7):1169-1178.
1,1-Bis(3'-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) activates the orphan receptor nerve growth factor-induced Bα (NGFI-Bα or Nur77) in cancer cells and, in this study, DIM-C-pPhOCH3 decreased Panc1 pancreatic cancer cell survival and arrested cells in G0/G1. These responses were accompanied by induction of the cyclin-dependent kinase inhibitor p21 in pancreatic cancer cells. Mechanistic studies demonstrated that induction of p21 mRNA and protein by DIM-C-pPhOCH3 was Nur77-dependent but did not depend on Krüppel-like factor-4 which was also induced by DIMC-pPhOCH3. Activation of p21 promoter constructs by DIM-C-pPhOCH3 required the GC-rich proximal region of the promoter, and results of RNA interference studies showed that Nur77-dependent activation of the p21 promoter involved interactions with Sp1 and Sp4 but not Sp3. Interactions of Nur77 with the p21 promoter in Panc1 cells treated with DIM-C-pPhOCH3 were also confirmed in chromatin immunoprecipitation assays. These data show that activation of nuclear Nur77 results in a novel pathway for induction of p21 which is independent of Nur77 response elements but dependent on Sp proteins bound to the GC-rich proximal region of the p21 promoter.
doi:10.1158/1541-7786.MCR-08-0473
PMCID: PMC2739813  PMID: 19584258
Nur77; activation; DIM analog; p21
10.  Apoptotic Effect of Tolfenamic Acid in KB Human Oral Cancer Cells: Possible Involvement of the p38 MAPK Pathway 
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to inhibit cancer growth by inhibiting the activity of cyclooxygenase (COX). However, there is increasing evidence that the COX-independent pathway may be also involved in the inhibitory effect of NSAIDs against tumor progression. Tolfenamic acid is a NSAID that exhibits anticancer activity in pancreatic and colorectal cancer models. In the present study, the anti-tumor effect of tolfenamic acid in KB human oral cancer cells is investigated. The results showed that tolfenamic acid does not alter the expression of the COX proteins, but it inhibits cell growth and induces apoptosis as evidenced by the annexin V positivity, sub-G1 population, nuclear fragmentation and the cleavage of poly ADP-ribose polymerase. In addition, tolfenamic acid also leads to a loss of the mitochondrial membrane potential in KB cells. These effects are related to the activation of p38 mitogen-activated protein kinase (MAPK) pathway. These results suggest that tolfenamic acid-induced apoptotic cell death inhibits cancer growth by activating the p38 MAPK pathway for cancer prevention.
doi:10.3164/jcbn.10-02
PMCID: PMC2901767  PMID: 20664734
KB human oral cancer cells; tolfenamic acid; mitochondrial membrane potential; apoptosis; p38 MAPK
11.  Cancer chemotherapy with indole-3-carbinol, bis(3′-indolyl)methane and synthetic analogs 
Cancer letters  2008;269(2):326-338.
Indole-3-carbinol (I3C) conjugates are phytochemicals expressed in brassica vegetables and have been associated with the anticancer activities of vegetable consumption. I3C and its metabolite bis(3′-indolyl)methane (DIM) induce overlapping and unique responses in multiple cancer cell lines and tumors, and these include growth inhibition, apoptosis and antiangiogenic activities. The mechanisms of these responses are complex and dependent on cell context. I3C and/or DIM activate or inactivate multiple nuclear receptors, induce endoplasmic reticulum stress, decrease mitochondrial membrane potential, and modulate multiple signaling pathways including kinases. DIM has been used as a template to synthesize a series of 1,1-bis(3′indolyl)-1-(substituted aromatic)methanes (i.e. C-DIMs) which are also cytotoxic to cancer cells and tumors. Some of the effects of C-DIMs resemble those reported for DIM analogs; however, structure–activity studies with the aromatic ring has resulted in generation of highly unique receptor agonists. For example, p-trifluoromethylphenyl, p-t-butylphenyl and p-biphenyl analogs activate peroxisome proliferator-activated receptor γ (PPARγ), and p-methoxyphenyl and p-phenyl compounds activate nerve growth factor-induced-Bα (NGFI-Bα, Nur77) orphan nuclear receptor. The effects of C-DIMs on PPARγ and Nur77 coupled with their receptor-independent activities has resulted in the development of a novel group of multi-targeted anticancer drugs with excellent potential for clinical treatment of cancer.
doi:10.1016/j.canlet.2008.04.021
PMCID: PMC2574232  PMID: 18501502
I3C; DIMs; Anticarcinogenesis; Nur77; PPAR
12.  1,1-Bis(3′-Indolyl)-1-(p-Substituted Phenyl)Methanes Decrease Mitochondrial Membrane Potential and Induce Apoptosis in Endometrial and Other Cancer Cell Lines 
Molecular carcinogenesis  2008;47(7):492-507.
1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes, containing p-t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) substituents, are peroxisome proliferator-activated receptor γ (PPARγ) agonists; however, DIM-C-pPhtBu-induced growth inhibition and cell death in human HEC1A endometrial cancer cells is PPARγ-independent. DIM-C-pPhtBu decreased mitochondrial membrane potential (MMP) and promoted the release of cytochrome c and caspase activation and nuclear uptake of endonuclease G leading to apoptosis of HEC1A cells. DIM-C-pPhtBu specifically targeted the mitochondrial permeability transition pore complex (PTPC) because the DIM-C-pPhtBu-induced proapoptotic responses were inhibited by atractyloside (Atra), a compound that specifically interacts with the inner mitochondrial membrane adenine nucleotide transport (ANT) proteins. At the dose of Atra used in this study (300 µM), this compound alone did not alter the PTPC but inhibited the mitochondriotoxic effects of DIM-C-pPhtBu. DIM-C-pPhtBu/DIM-C-pPhC6H5 and Atra also differentially affected the ability of eosin-5-maleimide (EMA) to alkylate Cys160 in the ANT protein and Atra, but not DIM-C-pPhtBu, inhibited the exchange of ATP/ADP in isolated mitochondria suggesting that these pharmacophores act on different sites on the ANT protein. Results of this study show that the receptor-independent proapoptotic activity of DIM-C-pPhtBu and DIM-C-pPhC6H5 were related to novel mitochondriotoxic activities involving inner mitochondrial ANT proteins.
doi:10.1002/mc.20407
PMCID: PMC2711558  PMID: 18085536
ANT; C-DIM; apoptosis; mitochondria; HEC1A cells
13.  CURCUMIN DECREASES SPECIFICITY PROTEIN (Sp) EXPRESSION IN BLADDER CANCER CELLS 
Cancer research  2008;68(13):5345-5354.
Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. In this study, 10 – 25 µM curcumin inhibited 253JB-V and KU7 bladder cancer cell growth, and this was accompanied by induction of apoptosis and decreased expression of the proapoptotic protein survivin and the angiogenic proteins vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Since expression of survivin, VEGF and VEGFR1 are dependent on specificity protein (Sp) transcription factors, we also investigated the effects of curcumin on Sp protein expression as an underlying mechanism for the apoptotic and antiangiogenic activity of this compound. The results show that curcumin induced proteasome-dependent downregulation of Sp1, Sp3 and Sp4 in 253JB-V and KU7 cells. Moreover, using RNA interference with small inhibitory RNAs for Sp1, Sp3 and Sp4, we observed that curcumin-dependent inhibition of nuclear factor κB (NFκB)-dependent genes such as bcl-2, survivin and cyclin D1, was also due, in part, to loss of Sp proteins. Curcumin also decreased bladder tumor growth in athymic nude mice bearing KU7 cells as xenografts and this was accompanied by decreased Sp1, Sp3 and Sp4 protein levels in tumors. These results demonstrate for the first time that one of the underlying mechanisms of action of curcumin as a cancer chemotherapeutic agent is due, in part, to decreased expression of Sp transcription factors in bladder cancer cells.
doi:10.1158/0008-5472.CAN-07-6805
PMCID: PMC2587449  PMID: 18593936
curcumin; Sp proteins; survivin; VEGF; VEGFR1; bladder cancer; inhibition
14.  5,5′-Dibromo-bis(3′-indolyl)methane induces Krüppel-like factor 4 and p21 in colon cancer cells 
Molecular cancer therapeutics  2008;7(7):2109-2120.
Bis(3′-indolyl)methane (DIM) is a metabolite of the phytochemical indole-3-carbinol, and both compounds exhibit a broad spectrum of anticancer activities. We have developed a series of synthetic symmetrical ring-substituted DIM analogues, including 5,5′-dibromoDIM, which are more potent than DIM as inhibitors of cancer cell and tumor growth. In colon cancer cells, 5,5′-dibromoDIM decreased cell proliferation and inhibited G0-G1- to S-phase progression, and this was accompanied by induction of the cyclin-dependent kinase inhibitor p21 in HT-29 and RKO colon cancer cells. Mechanistic studies showed that induction of p21 in both RKO (p53 wild-type) and HT-29 (p53 mutant) cells by 5,5′-dibromoDIM was Krüppel-like factor 4 (KLF4) dependent, and induction of p53 in RKO cells was also KLF4 dependent. Analysis of the p21 promoter in p53-dependent RKO cells showed that 5,5′-dibromoDIM activated p21 gene expression through the proximal GC-rich sites 1 and 2, and chromatin immunoprecipitation assays showed that KLF4 and p53 bound to this region of the promoter, whereas in HT-29 cells unidentified upstream cis-elements were required for induction of p21. 5,5′-DibromoDIM (30 mg/kg/d) also inhibited tumor growth and induced p21 in athymic nude mice bearing RKO cells as xenografts, showing that ring-substituted DIM such as 5,5′-dibromoDIM represent a novel class of mechanism-based drugs for clinical treatment of colon cancer.
doi:10.1158/1535-7163.MCT-07-2311
PMCID: PMC2565496  PMID: 18645021
15.  1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase 
Carcinogenesis  2008;29(6):1139-1147.
1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor γ (PPARγ) and Nur77 and induce receptor-dependent and -independent apoptotic pathways in colon and other cancer cells. Structure-activity studies show that the p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) analogs, which exhibit minimal activation of Nur77 and PPARγ, induce expression of CCAAT/enhancer-binding protein homologous protein (CHOP/GADD153) in colon cancer cells. Moreover, among a series of bromo and fluoro C-DIM analogs, their induction of CHOP was dependent on the position of the phenyl substituents (para ≥ meta ≥ ortho) and required a free indole group. DIM-C-pPhBr and DIM-C-pPhF not only induced CHOP but also activated death receptor 5 (CHOP dependent), cleavage of caspase 8 and poly (ADP ribose) polymerase (PARP) that is consistent with activation of the extrinsic pathway of apoptosis. These responses were associated with the activation of c-jun N-terminal kinase (JNK) pathway since inhibition of JNK inhibited induction of the extrinsic apoptotic pathway by these C-DIMs. However, in contrast to classical inducers of endoplasmic reticulum (ER) stress such as tunicamycin and thapsigargin, the C-DIM compounds did not induce glucose-related protein 78 that is a marker of ER stress. Proapoptotic and anticarcinogenic effects were also observed in athymic nude mice bearing RKO cell xenografts and treated with 30 mg/kg/day DIM-C-pPhBr and this was accompanied by increased JNK phosphorylation in the tumors. Thus, the anticarcinogenic activity of DIM-C-pPhBr in colon cancer cells and tumors is related to a novel ER stress-independent activation of JNK.
doi:10.1093/carcin/bgn103
PMCID: PMC2574736  PMID: 18460448
16.  1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes Inhibit Colon Cancer Cell and Tumor Growth Through Activation of c-Jun N-terminal Kinase 
Carcinogenesis  2008;29(6):1139-1147.
1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor γ (PPARγ) and Nur77, and induce receptor-dependent and -independent apoptotic pathways in colon and other cancer cells. Structure-activity studies show that the p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) analogs, which exhibit minimal activation of Nur77 and PPARγ, induce expression of CCAAT/enhancer binding protein homologous protein (CHOP/GADD153) in colon cancer cells. Moreover, among a series of bromo and fluoro C-DIM analogs, their induction of CHOP was dependent on the position of the phenyl substituents (para ≥ meta ≥ ortho) and required a free indole group. DIM-C-pPhBr and DIM-C-pPhF not only induced CHOP but also activated death receptor 5 (DR5) (CHOP-dependent), cleavage of caspase 8 and PARP which is consistent with activation of the extrinsic pathway of apoptosis. These responses were associated with activation of c-jun N-terminal kinase (JNK) pathway since inhibition of JNK inhibited induction of the extrinsic apoptotic pathway by these C-DIMs. However, in contrast to classical inducers of endoplasmic reticulum (ER) stress such as tunicamycin and thapsigargin, the C-DIM compounds did not induce glucose-related protein 78 (GRP78) which is a marker of ER stress. Proapoptotic and anticarcinogenic effects were also observed in athymic nude mice bearing RKO cell xenografts and treated with 30 mg/kg/d DIM-C-pPhBr and this was accompanied by increased JNK phosphorylation in the tumors. Thus, the anticarcinogenic activity of DIM-C-pPhBr in colon cancer cells and tumors is related to a novel ER stress-independent activation of JNK.
doi:10.1093/carcin/bgn103
PMCID: PMC2574736  PMID: 18460448
C-DIMs; growth inhibition; colon cancer; JNK activation; apoptosis

Results 1-16 (16)