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Ching-shih Chen - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological exploitation of Indole-3-Carbinol to develop potent antitumor agents.
Mini reviews in medicinal chemistry, 2010Co-Authors: Jing Ru Weng, Samuel K. Kulp, Hany A. Omar, Ching-shih ChenAbstract:The antitumor activity of Indole-3-Carbinol is attributable to its ability to interfere with multiple oncogenic signaling pathways governing cell cycle progression, survival, invasion, and other aggressive phenotypes of cancer cells, especially those mediated by EGFR/Src, Akt, NF-kB, endoplasmic reticulum stress, and nuclear receptors. This broad spectrum of antitumor activities in conjunction with its metabolic instability constitutes the rationale for the structural modifications of Indole-3-Carbinol and its metabolite diindoylmethane to develop novel classes of antitumor agents with improved potency and distinct mechanisms. Thus, this minireview focuses on the chemical biology of the lead optimization of these indole derivatives.
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OSU-A9, a potent Indole-3-Carbinol derivative, suppresses breast tumor growth by targeting the Akt–NF-κB pathway and stress response signaling
Carcinogenesis, 2009Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Dasheng Wang, Aaron M. Sargeant, Hany A. Omar, Charles L. Shapiro, Ching-shih ChenAbstract:The molecular heterogeneity of human tumors challenges the development of effective preventive and therapeutic strategies. To overcome this issue, a rational approach is the concomitant targeting of clinically relevant cellular abnormalities with combination therapy or a potent multi-targeted agent. OSU-A9 is a novel Indole-3-Carbinol derivative that retains the parent compound’s ability to perturb multiple components of oncogenic signaling, but provides marked advantages in chemical stability and antitumor potency. Here, we show that OSU-A9 exhibits two orders of magnitude greater potency than Indole-3-Carbinol in inducing apoptosis in various breast cancer cell lines with distinct genetic abnormalities, including MCF-7, MDA-MB-231 and SKBR3, with the half maximal inhibitory concentration in the range of 1.2– 1.8 mM vis-a `-vis 200 mM for Indole-3-Carbinol. This differential potency was paralleled by OSU-A9’s superior activity against multiple components of the Akt–nuclear factor-kappa B (NF-kB) and stress response signaling pathways. Notable among these were the increased estrogen receptor (ER)-b/ERa expression ratio, reduced expression of HER2 and CXCR4 and the upregulation of aryl hydrocarbon receptor expression and its downstream target NF-E2 p45-regulated factor (Nrf2). Non-malignant MCF10A cells were resistant to OSU-A9’s antiproliferative effects. Daily oral administration of OSU-A9 at 25 and 50 mg/kg for 49 days significantly inhibited MCF-7 tumor growth by 59 and 70%, respectively, without overt signs of toxicity or evidence of induced hepatic biotransformation enzymes. In summary, OSU-A9 is a potent, orally bioavailable inhibitor of the Akt–NF-kB signaling network, targeting multiple aspects of breast tumor pathogenesis and progression. Thus, its translational potential for the treatment or prevention of breast cancer warrants further investigation.
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Indole-3-Carbinol as a chemopreventive and anti-cancer agent.
Cancer letters, 2008Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Ching-shih ChenAbstract:During the course of oncogenesis and tumor progression, cancer cells constitutively upregulate signaling pathways relevant to cell proliferation and survival as a strategy to overcome genomic instability and acquire resistance phenotype to chemotherapeutic agents. In light of this clinical and molecular heterogeneity of human cancers, it is desirable to concomitantly target these genetic abnormalities by using an agent with pleiotropic mode of action. Indole-3-Carbinol and its metabolite 3,3'-diindoylmethane (DIM) target multiple aspects of cancer cell-cycle regulation and survival including Akt-NF kappa B signaling, caspase activation, cyclin-dependent kinase activities, estrogen metabolism, estrogen receptor signaling, endoplasmic reticulum stress, and BRCA gene expression. This broad spectrum of anti-tumor activities in conjunction with low toxicity underscores the translational value of Indole-3-Carbinol and its metabolites in cancer prevention/therapy. Furthermore, novel anti-tumor agents with overlapping underlying mechanisms have emerged via structural optimization of Indole-3-Carbinol and DIM, which may provide considerable therapeutic advantages over the parental compounds with respect to chemical stability and anti-tumor potency. Together, these agents might foster new strategies for cancer prevention and therapy.
Jing Ru Weng - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological exploitation of Indole-3-Carbinol to develop potent antitumor agents.
Mini reviews in medicinal chemistry, 2010Co-Authors: Jing Ru Weng, Samuel K. Kulp, Hany A. Omar, Ching-shih ChenAbstract:The antitumor activity of Indole-3-Carbinol is attributable to its ability to interfere with multiple oncogenic signaling pathways governing cell cycle progression, survival, invasion, and other aggressive phenotypes of cancer cells, especially those mediated by EGFR/Src, Akt, NF-kB, endoplasmic reticulum stress, and nuclear receptors. This broad spectrum of antitumor activities in conjunction with its metabolic instability constitutes the rationale for the structural modifications of Indole-3-Carbinol and its metabolite diindoylmethane to develop novel classes of antitumor agents with improved potency and distinct mechanisms. Thus, this minireview focuses on the chemical biology of the lead optimization of these indole derivatives.
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OSU-A9, a potent Indole-3-Carbinol derivative, suppresses breast tumor growth by targeting the Akt–NF-κB pathway and stress response signaling
Carcinogenesis, 2009Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Dasheng Wang, Aaron M. Sargeant, Hany A. Omar, Charles L. Shapiro, Ching-shih ChenAbstract:The molecular heterogeneity of human tumors challenges the development of effective preventive and therapeutic strategies. To overcome this issue, a rational approach is the concomitant targeting of clinically relevant cellular abnormalities with combination therapy or a potent multi-targeted agent. OSU-A9 is a novel Indole-3-Carbinol derivative that retains the parent compound’s ability to perturb multiple components of oncogenic signaling, but provides marked advantages in chemical stability and antitumor potency. Here, we show that OSU-A9 exhibits two orders of magnitude greater potency than Indole-3-Carbinol in inducing apoptosis in various breast cancer cell lines with distinct genetic abnormalities, including MCF-7, MDA-MB-231 and SKBR3, with the half maximal inhibitory concentration in the range of 1.2– 1.8 mM vis-a `-vis 200 mM for Indole-3-Carbinol. This differential potency was paralleled by OSU-A9’s superior activity against multiple components of the Akt–nuclear factor-kappa B (NF-kB) and stress response signaling pathways. Notable among these were the increased estrogen receptor (ER)-b/ERa expression ratio, reduced expression of HER2 and CXCR4 and the upregulation of aryl hydrocarbon receptor expression and its downstream target NF-E2 p45-regulated factor (Nrf2). Non-malignant MCF10A cells were resistant to OSU-A9’s antiproliferative effects. Daily oral administration of OSU-A9 at 25 and 50 mg/kg for 49 days significantly inhibited MCF-7 tumor growth by 59 and 70%, respectively, without overt signs of toxicity or evidence of induced hepatic biotransformation enzymes. In summary, OSU-A9 is a potent, orally bioavailable inhibitor of the Akt–NF-kB signaling network, targeting multiple aspects of breast tumor pathogenesis and progression. Thus, its translational potential for the treatment or prevention of breast cancer warrants further investigation.
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Indole-3-Carbinol as a chemopreventive and anti-cancer agent.
Cancer letters, 2008Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Ching-shih ChenAbstract:During the course of oncogenesis and tumor progression, cancer cells constitutively upregulate signaling pathways relevant to cell proliferation and survival as a strategy to overcome genomic instability and acquire resistance phenotype to chemotherapeutic agents. In light of this clinical and molecular heterogeneity of human cancers, it is desirable to concomitantly target these genetic abnormalities by using an agent with pleiotropic mode of action. Indole-3-Carbinol and its metabolite 3,3'-diindoylmethane (DIM) target multiple aspects of cancer cell-cycle regulation and survival including Akt-NF kappa B signaling, caspase activation, cyclin-dependent kinase activities, estrogen metabolism, estrogen receptor signaling, endoplasmic reticulum stress, and BRCA gene expression. This broad spectrum of anti-tumor activities in conjunction with low toxicity underscores the translational value of Indole-3-Carbinol and its metabolites in cancer prevention/therapy. Furthermore, novel anti-tumor agents with overlapping underlying mechanisms have emerged via structural optimization of Indole-3-Carbinol and DIM, which may provide considerable therapeutic advantages over the parental compounds with respect to chemical stability and anti-tumor potency. Together, these agents might foster new strategies for cancer prevention and therapy.
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A Potent Indole-3-Carbinol Derived Antitumor Agent with Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells
Cancer research, 2007Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Dasheng Wang, Chia-hui Lin, Hsiao-ching Yang, Aaron M. Sargeant, Chang Fang Chiu, Ming Hsui TsaiAbstract:Indole-3-Carbinol has emerged as a promising chemopreventive agent due to its in vivo efficacy in various animal models. However, Indole-3-Carbinol exhibits weak antiproliferative potency and is unstable in acidic milieu. Thus, this study was aimed at exploiting Indole-3-Carbinol to develop potent antitumor agents with improved chemical stability. This effort culminated in OSU-A9 {[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol}, which is resistant to acid-catalyzed condensation, and exhibits 100-fold higher apoptosis-inducing activity than the parent compound. Relative to Indole-3-Carbinol, OSU-A9 displays a striking qualitative similarity in its effects on the phosphorylation or expression of multiple signaling targets, including Akt, mitogen-activated protein kinases, Bcl-2 family members, survivin, nuclear factor-kappaB, cyclin D1, p21, and p27. The ability of OSU-A9 to concurrently modulate this broad range of signaling targets underscores its in vitro and in vivo efficacy in prostate cancer cells. Nevertheless, despite this complex mode of mechanism, normal prostate epithelial cells were less susceptible to the antiproliferative effect of OSU-A9 than PC-3 and LNCaP prostate cancer cells. Treatment of athymic nude mice bearing established s.c. PC-3 xenograft tumors with OSU-A9 at 10 and 25 mg/kg i.p. for 42 days resulted in a 65% and 85%, respectively, suppression of tumor growth. Western blot analysis of representative biomarkers in tumor lysates revealed significant reductions in the intratumoral levels of phosphorylated (p-) Akt, Bcl-xL, and RelA, accompanied by robust increases in p-p38 levels. In conclusion, the ability of OSU-A9 to target multiple aspects of cancer cell survival with high potency suggests its clinical value in prostate cancer therapy.
Raj K. Tiwari - One of the best experts on this subject based on the ideXlab platform.
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Anti-carcinogenic and anti-metastatic properties of Indole-3-Carbinol in prostate cancer
Oncology reports, 2005Co-Authors: V. P. S. Garikapaty, Badithe T. Ashok, Yuangen Chen, Abraham Mittelman, M. Iatropoulos, Raj K. TiwariAbstract:Indole-3-Carbinol (I3C), a compound present as glucobracissin in cruciferous vegetables has anticancer activities which is in line with some of the epidemiological evidence that suggests a beneficial effect of consumption of cruciferous vegetables on cancer incidence and progression. The precise target of Indole-3-Carbinol has not been determined. We examined the effect of I3C on prostate cancer in a well-defined R3327 model using Copenhagen rats and the transplantable cell line, MAT-LyLu. This cell line derived from a tumor in Copenhagen rats is androgen independent and metastasizes to the lung and lymph nodes. Tumors were induced in Copenhagen rats by injecting MAT-LyLu subcutaneously and the animals treated with I3C that was administered either intraperitoneally or intravenously, in order to achieve maximal systemic exposure. This was a departure from the traditional chemopreventive route of Indole-3-Carbinol where the compound was incorporated in the diet. Our results indicate that I3C inhibited the incidence, growth and metastases of MAT-LyLu cells and both i.p. and i.v. injections of I3C were equally effective. Statistical analysis (Kaplan-Meier curves) clearly indicates a tumor-free and overall survival benefit as a result of treatment with I3C. These studies show for the first time that I3C in an injectible form has anti-prostate cancer activity.
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Abrogation of Estrogen-Mediated Cellular and Biochemical Effects by Indole-3-Carbinol
Nutrition and Cancer, 2001Co-Authors: Badithe T. Ashok, H. Leon Bradlow, Yuangen Chen, Abraham Mittelman, Xinyan Liu, Raj K. TiwariAbstract:The use of naturally occurring phytoantiestrogens for prevention and therapy of breast cancer is an alternative to synthetic antiestrogens. We have been examining the mechanism of action of the antiestrogen Indole-3-Carbinol (I3C), a constituent of compounds present in cruciferous vegetables. I3C abrogates the cell-proliferative effect of 17β-estradiol (E2), as observed in several different estradiol-responsive breast cancer cell lines and isolated cell clones. Modulation of E2 activity by I3C, in part, was by the induction of the 2-hydroxylation pathway, one of the two competing hydroxylation pathways of estrone conversion that resulted in the formation of metabolites with antiestrogenic properties. I3C-mediated induction of the 2-hydroxylation pathway correlated with a selective induction of cytochrome P-450 1A1 by I3C in E2-responsive human breast cancer cells. Induction of neither the 2-hydroxylation pathway nor cytochrome P-450 1A1 was observed in estrogen-nonresponsive human breast cancer cells. Thi...
H. Leon Bradlow - One of the best experts on this subject based on the ideXlab platform.
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Abrogation of Estrogen-Mediated Cellular and Biochemical Effects by Indole-3-Carbinol
Nutrition and Cancer, 2001Co-Authors: Badithe T. Ashok, H. Leon Bradlow, Yuangen Chen, Abraham Mittelman, Xinyan Liu, Raj K. TiwariAbstract:The use of naturally occurring phytoantiestrogens for prevention and therapy of breast cancer is an alternative to synthetic antiestrogens. We have been examining the mechanism of action of the antiestrogen Indole-3-Carbinol (I3C), a constituent of compounds present in cruciferous vegetables. I3C abrogates the cell-proliferative effect of 17β-estradiol (E2), as observed in several different estradiol-responsive breast cancer cell lines and isolated cell clones. Modulation of E2 activity by I3C, in part, was by the induction of the 2-hydroxylation pathway, one of the two competing hydroxylation pathways of estrone conversion that resulted in the formation of metabolites with antiestrogenic properties. I3C-mediated induction of the 2-hydroxylation pathway correlated with a selective induction of cytochrome P-450 1A1 by I3C in E2-responsive human breast cancer cells. Induction of neither the 2-hydroxylation pathway nor cytochrome P-450 1A1 was observed in estrogen-nonresponsive human breast cancer cells. Thi...
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Quantitative Determination of 3,3?-Diindolylmethane inUrine of Individuals Receiving Indole-3-Carbinol
Nutrition and Cancer, 2001Co-Authors: W. Daniel, H. Leon Bradlow, Sepkovic, Maria C. BellAbstract:Indole-3-Carbinol (I3C) or, more correctly, its acid condensation products act as chemoprotective agents via several mechanisms. It induces the expression of cytochrome P-450 1A1, which shifts the estrogen metabolic pathway in favor of C-2 hydroxylation and away from the formation of 16 α-hydroxyestrone, a suspected endogenous carcinogen. Increased 16 α-hydroxylation of estrogen is associated with greater risk of cancer of the cervix, breast, endometrium, and larynx. The production of 4-hydroxyestrone is also inhibited by I3C. I3C can induce a G1 cell cycle arrest in human MCF-7 breast cancer cells. It can suppress aberrant crypt foci. I3C significantly inhibits the cell adhesion, spreading, and invasion associated with an upregulation of PTEN (a tumor suppressor gene) and E-cadherin (a regulator of cell-cell adhesion) expression in T47-D human breast cancer cells. Thus I3C exhibits anticancer activities by suppressing breast tumor cell growth and metastatic spread. A gas chromatography-mass spectrometry ...
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Preliminary results of the use of Indole-3-Carbinol for recurrent respiratory papillomatosis
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery, 1998Co-Authors: Clark A. Rosen, Gayle E. Woodson, Jerome W. Thompson, Arne Hengesteg, H. Leon BradlowAbstract:We report the preliminary results of a phase I trial using Indole-3-Carbinol for the treatment of recurrent respiratory papillomatosis. Indole-3-Carbinol is a chemical that is found in high concentrations in cruciferous vegetables and has been shown to alter the growth pattern of recurrent respiratory papillomatosis cell cultures and to be effective in an in vivo animal model of recurrent respiratory papillomatosis. Eighteen patients were treated with oral Indole-3-Carbinol and had a minimum follow-up of 8 months and a mean follow-up of 14.6 months. All patients received Indole-3-Carbinol, and outcome measures included a change in papilloma growth rate and the need for surgery during treatment compared with before treatment. All patients had serial examinations with videoendoscopy to document papilloma location and growth rate. Thirty-three percent (6 of 18) of the study patients had a cessation of their papilloma growth and have not required surgery since the start of the study. Six patients have had reduced papilloma growth rate, and 6 (33%) patients have shown no clinical response to Indole-3-Carbinol. Indole-3-Carbinol affects the ratio of hydroxylation of estradiol; changes in the ratios of urinary 2-hydroxylation and 16-hydroxylation of estradiol caused by Indole-3-Carbinol correlated well with clinical response. No major complications or changes in the children's growth curve were noted. The preliminary results of treating recurrent respiratory papillomatosis with Indole-3-Carbinol holds promise. Longer follow-up of this patient group and a blinded, controlled trial are required. We conclude that Indole-3-Carbinol appears to be safe and well tolerated and may be an efficacious treatment for recurrent respiratory papillomatosis.
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Indole-3-Carbinol. A novel approach to breast cancer prevention.
Annals of the New York Academy of Sciences, 1995Co-Authors: H. Leon Bradlow, D. W. Sepkovic, Nitin T. Telang, Michael P. OsborneAbstract:The results show that all of the carcinogens, oncogenes, and tumor-associated viruses that we have studied profoundly affect the extent of 2- and 16 alpha-hydroxylation in a prorisk direction. All of the dietary and biological responses associated with increased cancer risk decrease 2-hydroxylation and increase 16 alpha-hydroxylation. Remarkably, although PAHs are reported to induce P450-1A1, we have found them to decrease 2-hydroxylation. Finally, using Indole-3-Carbinol to induce 2-hydroxylation results in the chemoprevention of mammary tumors in rodents and recurrences of laryngeal papillomas in humans. Also correlating with these studies in HPV is the decrease in the C-2/C-16 alpha metabolite ratio observed in women with CIN relative to control subjects. The greatest decrease was observed in women with the most severe form, CIN3 (Figure 23). These findings are under further investigation.
Samuel K. Kulp - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological exploitation of Indole-3-Carbinol to develop potent antitumor agents.
Mini reviews in medicinal chemistry, 2010Co-Authors: Jing Ru Weng, Samuel K. Kulp, Hany A. Omar, Ching-shih ChenAbstract:The antitumor activity of Indole-3-Carbinol is attributable to its ability to interfere with multiple oncogenic signaling pathways governing cell cycle progression, survival, invasion, and other aggressive phenotypes of cancer cells, especially those mediated by EGFR/Src, Akt, NF-kB, endoplasmic reticulum stress, and nuclear receptors. This broad spectrum of antitumor activities in conjunction with its metabolic instability constitutes the rationale for the structural modifications of Indole-3-Carbinol and its metabolite diindoylmethane to develop novel classes of antitumor agents with improved potency and distinct mechanisms. Thus, this minireview focuses on the chemical biology of the lead optimization of these indole derivatives.
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OSU-A9, a potent Indole-3-Carbinol derivative, suppresses breast tumor growth by targeting the Akt–NF-κB pathway and stress response signaling
Carcinogenesis, 2009Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Dasheng Wang, Aaron M. Sargeant, Hany A. Omar, Charles L. Shapiro, Ching-shih ChenAbstract:The molecular heterogeneity of human tumors challenges the development of effective preventive and therapeutic strategies. To overcome this issue, a rational approach is the concomitant targeting of clinically relevant cellular abnormalities with combination therapy or a potent multi-targeted agent. OSU-A9 is a novel Indole-3-Carbinol derivative that retains the parent compound’s ability to perturb multiple components of oncogenic signaling, but provides marked advantages in chemical stability and antitumor potency. Here, we show that OSU-A9 exhibits two orders of magnitude greater potency than Indole-3-Carbinol in inducing apoptosis in various breast cancer cell lines with distinct genetic abnormalities, including MCF-7, MDA-MB-231 and SKBR3, with the half maximal inhibitory concentration in the range of 1.2– 1.8 mM vis-a `-vis 200 mM for Indole-3-Carbinol. This differential potency was paralleled by OSU-A9’s superior activity against multiple components of the Akt–nuclear factor-kappa B (NF-kB) and stress response signaling pathways. Notable among these were the increased estrogen receptor (ER)-b/ERa expression ratio, reduced expression of HER2 and CXCR4 and the upregulation of aryl hydrocarbon receptor expression and its downstream target NF-E2 p45-regulated factor (Nrf2). Non-malignant MCF10A cells were resistant to OSU-A9’s antiproliferative effects. Daily oral administration of OSU-A9 at 25 and 50 mg/kg for 49 days significantly inhibited MCF-7 tumor growth by 59 and 70%, respectively, without overt signs of toxicity or evidence of induced hepatic biotransformation enzymes. In summary, OSU-A9 is a potent, orally bioavailable inhibitor of the Akt–NF-kB signaling network, targeting multiple aspects of breast tumor pathogenesis and progression. Thus, its translational potential for the treatment or prevention of breast cancer warrants further investigation.
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Indole-3-Carbinol as a chemopreventive and anti-cancer agent.
Cancer letters, 2008Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Ching-shih ChenAbstract:During the course of oncogenesis and tumor progression, cancer cells constitutively upregulate signaling pathways relevant to cell proliferation and survival as a strategy to overcome genomic instability and acquire resistance phenotype to chemotherapeutic agents. In light of this clinical and molecular heterogeneity of human cancers, it is desirable to concomitantly target these genetic abnormalities by using an agent with pleiotropic mode of action. Indole-3-Carbinol and its metabolite 3,3'-diindoylmethane (DIM) target multiple aspects of cancer cell-cycle regulation and survival including Akt-NF kappa B signaling, caspase activation, cyclin-dependent kinase activities, estrogen metabolism, estrogen receptor signaling, endoplasmic reticulum stress, and BRCA gene expression. This broad spectrum of anti-tumor activities in conjunction with low toxicity underscores the translational value of Indole-3-Carbinol and its metabolites in cancer prevention/therapy. Furthermore, novel anti-tumor agents with overlapping underlying mechanisms have emerged via structural optimization of Indole-3-Carbinol and DIM, which may provide considerable therapeutic advantages over the parental compounds with respect to chemical stability and anti-tumor potency. Together, these agents might foster new strategies for cancer prevention and therapy.
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A Potent Indole-3-Carbinol Derived Antitumor Agent with Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells
Cancer research, 2007Co-Authors: Jing Ru Weng, Chen Hsun Tsai, Samuel K. Kulp, Dasheng Wang, Chia-hui Lin, Hsiao-ching Yang, Aaron M. Sargeant, Chang Fang Chiu, Ming Hsui TsaiAbstract:Indole-3-Carbinol has emerged as a promising chemopreventive agent due to its in vivo efficacy in various animal models. However, Indole-3-Carbinol exhibits weak antiproliferative potency and is unstable in acidic milieu. Thus, this study was aimed at exploiting Indole-3-Carbinol to develop potent antitumor agents with improved chemical stability. This effort culminated in OSU-A9 {[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol}, which is resistant to acid-catalyzed condensation, and exhibits 100-fold higher apoptosis-inducing activity than the parent compound. Relative to Indole-3-Carbinol, OSU-A9 displays a striking qualitative similarity in its effects on the phosphorylation or expression of multiple signaling targets, including Akt, mitogen-activated protein kinases, Bcl-2 family members, survivin, nuclear factor-kappaB, cyclin D1, p21, and p27. The ability of OSU-A9 to concurrently modulate this broad range of signaling targets underscores its in vitro and in vivo efficacy in prostate cancer cells. Nevertheless, despite this complex mode of mechanism, normal prostate epithelial cells were less susceptible to the antiproliferative effect of OSU-A9 than PC-3 and LNCaP prostate cancer cells. Treatment of athymic nude mice bearing established s.c. PC-3 xenograft tumors with OSU-A9 at 10 and 25 mg/kg i.p. for 42 days resulted in a 65% and 85%, respectively, suppression of tumor growth. Western blot analysis of representative biomarkers in tumor lysates revealed significant reductions in the intratumoral levels of phosphorylated (p-) Akt, Bcl-xL, and RelA, accompanied by robust increases in p-p38 levels. In conclusion, the ability of OSU-A9 to target multiple aspects of cancer cell survival with high potency suggests its clinical value in prostate cancer therapy.