OSU-A9, a potent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt-NF-kappaB pathway and stress response signaling.
OSU-A9, a potent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt-NF-kappaB pathway and stress response signaling.
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DOI：
10.1093/carcin/bgp202
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发表时间：
2009-10
期刊：
影响因子：
4.7
通讯作者：
J. Weng;Chen-Hsun Tsai;H. Omar;A. Sargeant;Dasheng Wang;S. Kulp;C. Shapiro;Ching S. Chen
中科院分区：
文献类型：
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作者：
J. Weng;Chen-Hsun Tsai;H. Omar;A. Sargeant;Dasheng Wang;S. Kulp;C. Shapiro;Ching S. Chen
人类肿瘤的分子异质性挑战了有效预防和治疗策略的发展。为了克服这个问题，一个合理的方法是联合治疗或强效多靶点药物同时靶向临床相关的细胞异常。OSU-A9是一种新型的吲哚-3-甲醇衍生物，它保留了母体化合物干扰多种致癌信号成分的能力，但在化学稳定性和抗肿瘤效力方面具有显著优势。在这里，我们发现OSU-A9在诱导多种具有不同遗传异常的乳腺癌细胞系（包括MCF-7、MDA-MB-231和SKBR3）的细胞凋亡方面表现出比吲哚-3-甲醇高两个数量级的效能，其中一半最大抑制浓度在1.2-1.8微米范围内，而吲哚-3-甲醇的抑制浓度为-à-vis 200微米。这种差异效力与OSU-A9对akt -核因子- κ B （nf - κ B）和应激反应信号通路的多种组分的优越活性相一致。其中值得注意的是雌激素受体(ER)- β /ER - α表达比升高，HER2和CXCR4表达降低，芳烃受体及其下游靶点NF-E2 p45调节因子（Nrf2）表达上调。非恶性MCF-10A细胞对OSU-A9的抗增殖作用有抵抗性。每天口服25和50 mg/kg的OSU-A9，连续49天，分别显著抑制了59%和70%的MCF-7肿瘤生长，没有明显的毒性迹象或诱导肝脏生物转化酶的证据。总之，OSU-A9是一种有效的口服生物可利用的Akt-NF-kappaB信号网络抑制剂，针对乳腺肿瘤发病和进展的多个方面。因此，它在治疗或预防乳腺癌方面的转化潜力值得进一步研究。
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.