A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis

// Liping Xiang 1 , Ting Chi 1 , Qiao Tang 1 , Xiang Yang 1 , Minrui Ou 1 , Xiufen Chen 1 , Xiaobo Yu 1 , Jianzhong Chen 2 , Rodney J.Y. Ho 3 , Jingwei Shao 1 , Lee Jia 1 1 Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350002, China 2 School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350108, China 3 Department of Pharmaceutics, University of Washington, Seattle, WA 98105, USA Correspondence to: Jingwei Shao, e-mail: shaojingwei@fzu.edu.cn Keywords: Anti-metastasis, ursolic acid, cell adhesion molecules, integrin, focal adhesion Received: December 23, 2014      Accepted: January 30, 2015      Published: March 19, 2015 ABSTRACT Here we showed that ursolic acid (UA), a pentacyclic triterpene natural product, and its novel prodrug derivative US597 suppressed cancer cells adhesion, invasion and migration. This effect was accompanied by inhibition of focal adhesion signaling pathway including alterations in ICAM-1, VCAM-1, E-selectin, P-selectin, integrin α6β1, FAK, Src, paxillin and PTEN. While oral administration of UA or US597 increases survival rate of melanoma lung metastasis in C57BL/6 mice, US597 treatment extend the survival rate above that of UA. Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis. We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities. Thus, UA and US597 are potential drug candidates for preventing cancer metastasis. Molecular and cellular study data suggest that UA and US597 modulate expression of cell adhesion molecules within focal adhesion signaling pathway leading to cancer cell motility.