Abstract A23: Daurinol suppresses human cancer metastasis by inhibition of focal adhesion kinase (FAK) signaling pathways

Background and Purpose: Globally most of the cancers associated with mortality and morbidity arise from metastatic spread of primary tumors. Traditional anti-cancer drugs mostly focus on inhibiting tumor cell growth or killing tumor cells directly or indirectly; however, there are only a few drugs that specifically inhibit metastasis of tumor cells. Noteworthy, the focal adhesive kinase (FAK) plays an important role in cytoskeleton remodeling and in regulating the tumor cell invasiveness and metastasis. The FAK is a tyrosine kinase that is localized to cellular focal adhesions and is associated with a number of other proteins, such as the integrin adhesion receptors clusters called focal adhesions. FAK overexpression has been detected in diverse primary and metastatic tumor tissues, supporting its pro-tumorigenic and pro-metastatic roles. Daurinol, which is a natural compound purified from Haplophyllum dauricum, has historically been used to treat tumors. Anti-proliferative activities of daurinol against various human cancer cells have been reported and daurinol displayed strong anti-tumor activity without any significant adverse effects. Therefore, we have developed a neo-treatment strategy with daurinol to effectively treat cancer. Herein, we extend our knowledge with the characterization of daurinol, an inhibitor of metastasis which blocks FAK signaling in breast and lung cancer. Results: Daurinol blocked cancer cell migration and invasion in in vitro and exhibited anti-metastatic activity in orthotopic breast cancer and xenograft lung cancer mouse models. Daurinol (10 mg/kg; Oral gavage) inhibited effectively breast and lung metastasis. Consistently with these in vivo results, a relatively low concentration of daurinol suppressed cell migration and Invasion in MDA-MB-231 and A549 human cancer cells. These data were associated with inhibition of invasion factors, such as matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion. Daurinol also significantly decreased the tumor development in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) / benzo(a)pyrene (BaP)-treated A/J mice. Daurinol showed strong growth suppressive activity as revealed by colony formation assays. In addition, daurinol selectively inhibited the phosphorylation of FAK at Tyr925, Tyr 576/577, and Tyr 397 sites in a dose- and time-dependent manner. Analysis of cellular phenotypes revealed that the inhibition of FAK phosphorylation in cancer cells limits their colony-formation, cell migration and invasion less affecting cell proliferation rate. These data suggest that the effects of daurinol on metastasis and tumor development in cancer cells are restricted in cellular survival machinery. Conclusion: Our results suggest that daurinol suppresses lung metastasis through inhibition of migration and survival via blockade of FAK activity. However, it still remains to be seen whether daurinol has direct anticancer actions in clinics. Citation Format: Jong Kyu Woo, Ji-Youn Park, Chu Won Nho, Seung Hyun Oh. Daurinol suppresses human cancer metastasis by inhibition of focal adhesion kinase (FAK) signaling pathways. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A23.