title: OSU-A9, a potent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt-NF-kappaB pathway and stress response signaling.
abstract: 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 microM vis-à-vis 200 microM 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-kappaB) and stress response signaling pathways. Notable among these were the increased estrogen receptor (ER)-beta/ERalpha 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-kappaB 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.
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
authors.forename: Chen-Hsun
authors.initials: CH
authors.lastname: Tsai
authors.forename: Hany A
authors.initials: HA
authors.lastname: Omar
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Sargeant
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008156:Luciferases / Q000235:genetics; D000432:Methanol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016328:NF-kappa B / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C523234:(1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl)-methanol; D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007211:Indoles; D016328:NF-kappa B; D008156:Luciferases; D051057:Proto-Oncogene Proteins c-akt; D000432:Methanol
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