A Potent Indole-3-Carbinol–Derived Antitumor Agent with Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells

Abstract

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-KB, 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. [Cancer Res 2007;67(16):7815-24]

Indole-3-carbinol Suppresses Tumor-Induced Angiogenesis by Inhibiting Tube Formation and Inducing Apoptosis

“…8,10,11) Our results also showed that, against HUVECs, I3C failed to affect cell growth at the concentration which was sufficient to inhibit tube formation and induce apoptosis in the tube-forming endothelial cells. Tube-forming endothelial cells have been reported to function and express genes/proteins that are closer to those observed in vivo than dishcultured endothelial cells.…”

Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

“…The overexpression of Survivin in these tumors may be due to an autoregulation of its own synthesis or a result of a loss of control over Stat3 (by GRIM-19), which is known to induce Survivin. 32 Similarly, RT-PCR and Western blot results also showed that Survivin was highly upregulated in PCa tissue and prostatic DU145 cells while GRIM-19 was severely depressed (P,0.01) (Supplementary Figure 1b-e). The expression levels of Survivin and GRIM-19 in tumors were significantly different from those found in normal tissues (Supplementary Tables 2 and 3).…”

Development of a Simple Method for Determination of Anti-cancer Component of Indole-3-carbinol in Cabbage and Broccoli

“…Recovery was carried out by known cabbage samples spiked with indole-3-carbinol at concentrations of 10 . The determination of detection limits (LODs) and quantification limits (LOQs) was performed by analysis of the decrease in the concentration of the standard solutions.…”

“…Epidemiological and clinical studies suggest that indole-3-carbinol is a potential agent in blocking tumour initiation, oestrogen metabolism, inhibition of cell proliferation and induction of apoptosis [3,4,5,6,7]. So far, many studies have shown indole-3-carbinol is a bioactive component that plays an important anti-cancer role against breast [8], liver [9], prostate [10], lung and colon cancers [11,12]. Thus, indole-3-carbinol has been widely studied and has proved to be a potentially useful agent in cancer prevention.…”