Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Pigment Cell Melanoma Res. 2011 Aug;24(4):703-13. doi: 10.1111/j.1755-148X.2011.00867.x. Epub 2011 Jun 6.
In melanoma, the activation of pro-survival signaling pathways, such as the AKT and NF-κB pathways, is critical for tumor growth. We have recently reported that the AKT inhibitor BI-69A11 causes efficient inhibition of melanoma growth. Here, we show that in addition to its AKT inhibitory activity, BI-69A11 also targets the NF-κB pathway. In melanoma cell lines, BI-69A11 inhibited TNF-α-stimulated IKKα/β and IκB phosphorylation as well as NF-κB reporter gene expression. Furthermore, the effective inhibition of melanoma growth by BI-69A11 was attenuated upon NF-κB activation. Mechanistically, reduced NF-κB signaling by BI-69-A11 is mediated by the inhibition of sphingosine kinase 1, identified in a screen of 315 kinases. Significantly, we demonstrate that BI-69A11 is well tolerated and orally active against UACC 903 and SW1 melanoma xenografts. Our results demonstrate that BI-69A11 inhibits both the AKT and the NF-κB pathways and that the dual targeting of these pathways may be efficacious as a therapeutic strategy in melanoma.
在黑色素瘤中，促生存信号通路（如 AKT 和 NF-κB 通路）的激活对于肿瘤生长至关重要。我们最近报道 AKT 抑制剂 BI-69A11 可有效抑制黑色素瘤生长。在这里，我们表明除了其 AKT 抑制活性外，BI-69A11 还靶向 NF-κB 通路。在黑色素瘤细胞系中，BI-69A11 抑制 TNF-α 刺激的 IKKα/β 和 IκB 磷酸化以及 NF-κB 报告基因表达。此外，BI-69A11 通过 NF-κB 激活有效抑制黑色素瘤生长。在机制上，BI-69-A11 通过抑制在 315 种激酶筛选中鉴定的鞘氨醇激酶 1 来介导 NF-κB 信号的减少。重要的是，我们证明 BI-69A11 对 UACC 903 和 SW1 黑色素瘤异种移植物具有良好的耐受性和口服活性。我们的结果表明 BI-69A11 抑制 AKT 和 NF-κB 通路，并且靶向这些通路的双重作用可能是黑色素瘤治疗策略的有效方法。
