Research Center for Industry of Human Ecology, ‡Graduate Institute of Health Industry Technology, and §Department of Nutrition and Health Sciences, Chang Gung University of Science and Technology , Kwei-San, Tao-Yuan, Taiwan.
J Med Chem. 2014 Feb 13;57(3):677-85. doi: 10.1021/jm401686b. Epub 2014 Jan 31.
Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibits the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo antitumor and antimetastasis activities against subcutaneous and orthotopic xenografts of CL1-5 cells in nude mice. Chemical proteomics showed that heat shock protein 90 (HSP90) and heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) bound PBT-1 in CL1-5 cells. Inhibition of HSP90 and hnRNP A2/B1 reduced the activation of AKT and Slug expression. Taken together, these findings suggest that PBT-1 binds to HSP90 and/or hnRNP A2/B1 and initiates antitumor activities by affecting Slug- and AKT-mediated metastasis and tumorigenesis.
天然产物是目前可用的抗癌药物的主要来源。我们最近报道，基于菲的千里光碱衍生物-1（PBT-1）可能是肺腺癌的一种潜在抗肿瘤药物。因此，我们研究了 PBT-1 的直接靶标及其在抑制肺腺癌中的作用。我们发现 PBT-1 降低了 Slug 的水平，并抑制了肺腺癌细胞 CL1-5 的体外迁移、侵袭和丝状伪足形成。此外，PBT-1 在裸鼠的 CL1-5 细胞皮下和原位异种移植中表现出体内抗肿瘤和抗转移活性。化学蛋白质组学表明，热休克蛋白 90（HSP90）和异质核核糖核蛋白 A2/B1（hnRNP A2/B1）在 CL1-5 细胞中与 PBT-1 结合。抑制 HSP90 和 hnRNP A2/B1 降低了 AKT 的激活和 Slug 的表达。综上所述，这些发现表明，PBT-1 结合 HSP90 和/或 hnRNP A2/B1，并通过影响 Slug 和 AKT 介导的转移和肿瘤发生来启动抗肿瘤活性。
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