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.