MEDI 337 |
| Purpose. The chemopreventive potential of indole-3-carbinol has attracted much attention because of its demonstrated ability to protect against chemical-induced carcinogenesis in different experimental animal models. From a mechanistic perspective, the ability of indole-3-carbinol to target a broad range of signaling pathways underlies its translational potential for cancer prevention and/or treatment. Therefore, this study was aimed at pharmacologically exploiting indole-3-carbinol as a molecular platform to develop structural variants with improved chemical stability and apoptosis-inducing potency. Methods. Structural optimization was carried out by structure-activity correlations in conjunction with molecular modeling. The in vitro effects of structural variants vis-à-vis indole-3-carbinol were evaluated in PC-3 and LNCaP human prostate cancer cell lines. Cell viability, apoptosis, and signaling targets were determined by immunoblotting, and chemical stability was assessed by nuclear magnetic resonance spectrometry. Results. Among a series of indole-3-carbinol derivatives examined, OSUMC-A9 represented the optimal agent with IC50 of 2 µM and 3.8 µM for reducing the viability of PC-3 and LNCaP cells, respectively, which were two-order-of-magnitude lower than that of indole-3-carbinol (respective IC50, 512 µM and 267 µM). Despite a 100-fold difference in antitumor potency, the pharmacological profiles of OSUMC-A9 and indole-3-carbinol in interfering with target signaling pathways were virtually identical. Both agents facilitated dose-dependent dephosphorylation of Akt and its substrates GSK3 and Bad, accompanied by increased phosphorylation of MAP kinases. Moreover, the effects of OSUMC-A9 on suppressing the expression of Bcl-2, Bcl-xL, Mcl-1, survivin, NF-kB, and cyclin D1, and on up-regulating the expression of Bax, p27, and p21 paralleled those of indole-3-carbinol. The growth of existing PC-3 tumor xenografts was completely suppressed after i.p. treatment with OSUMC-A9 at 25 mg/kg. Conclusion. OSUMC-A9 is a potent antitumor agent with pleotropic mode of mechanisms by affecting multiple signaling pathways, which might have translational potential in cancer therapy. |
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |