Carcinogenesis Advance Access originally published online on August 25, 2009
Carcinogenesis 2009 30(10):1702-1709; doi:10.1093/carcin/bgp202
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OSU-A9, a potent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt–NF-
B pathway and stress response signaling
Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan
1 Division of Medicinal Chemistry, College of Pharmacy
2 Department of Veterinary Biosciences, College of Veterinary Medicine
3 Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
* To whom correspondence should be addressed. Division of Medicinal Chemistry, College of Pharmacy, Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 4008; Fax: +1 614 688 8556; Email: chen.844{at}osu.edu
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-
B) and stress response signaling pathways. Notable among these were the increased estrogen receptor (ER)-β/ER
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-B 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.
Abbreviations: AhR, aryl hydrocarbon receptor; DMSO, dimethyl sulfoxide; ER, estrogen receptor; FBS, fetal bovine serum; GSK, glycogen synthase kinase; IKK, IB kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; NF-B, nuclear factor-kappa B; Nrf2, NF-E2 p45-regulated factor; PBS, phosphate-buffered saline; PARP, poly(adenine dinucleotide phosphate–ribose) polymerase; TBST, Tris-buffered saline containing 0.05% Tween 20
Received April 7, 2009; revised July 7, 2009; accepted August 1, 2009.