Jing-Ru Weng, Chen-Hsun Tsai, Hany A. Omar, Aaron M. Sargeant, Dasheng Wang, Samuel K. Kulp, Charles L. Shapiro, and Ching-Shih Chen. OSU-A9, a Potent Indole-3-Carbinol Derivative, Suppresses Breast Tumor Growth by Targeting the Akt-NF-κB Pathway and Stress Response Signaling. Carcinogenesis, 2009 Oct;30(10):1702-9

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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 μM vis-à-vis 200 μM 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-κB) and stress response signaling pathways. Notable among these were the increased estrogen receptor (ER)-β/ERα 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 MCF-10A 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-κB 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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