Abstract P3-06-09: Discovery of novel oridonin-derivatives for the treatment of metastatic breast cancer

Abstract

Abstract Metastasis to other organs is the major cause of death from breast cancer. The 5-year survival rate is approximately 99% for localized breast cancer, but sharply drops to approximately 26% for patients with distant metastasis. However, there are currently no effective, targeted therapies available for treating metastatic breast cancer. Oridonin, a complex ent-kaurane diterpenoid isolated from Chinese traditional herb Rabdosia rubescens, has demonstrated great potential in the treatment of various human cancers. However, relatively low aqueous solubility and bioavailability limited its development into clinical applications. Herein, a number of novel nitrogen-enriched heterocyclic oridonin derivatives and dienone analogs such as YD0514, CYD0618, and CYD0686 have been generated from oridonin. These derivative analogs showed improved anti-proliferation effects against breast cancer cells, compared to oridonin. YD0514, CYD0618, and CYD0686 also displayed significant suppression of migration and invasion in MDA-MB-231 cell, a highly metastatic triple-negative breast cancer cell line. Furthermore, YD0514, CYD0618 and CYD0686 also inhibited the endothelial adhesion of GI101 and its derived, highly metastatic sublines, to the endothelium. We next found that YD0514, CYD0618, and CYD0686 can significantly inhibit the expression and phosphorylation of FAK and block the expression of integrin family members in those highly metastatic breast cancer cell lines. Further pathway analysis demonstrated that YD0514, CYD0618, and CYD0686 inhibited cellular motility potentially by decreasing RHOA/ROCK signaling pathway. Our findings suggest that novel oridonin-derivatives, YD0514, CYD0618, and CYD0686 have the great potential to be developed as effective therapeutics for the treatment of metastatic breast cancer. This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), and Holden Family Research Grant in BC Prevention (QS). Citation Format: Li D, Zhang Z, Ding Y, Zheng Z, Dong J, Kim H, Xu J, Chen H, Zhou J, Shen Q. Discovery of novel oridonin-derivatives for the treatment of metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-06-09.