Abstract 5573: Discovery of potent oridonin derivatives for the treatment of breast cancer.

Oridonin, a diterpenoid derived from the herbal Rabdosia rubescens, has been reported to have antitumor effects on various types of cancer cells. However, its relatively low aqueous solubility and bioavailability have limited its development into clinical applications. Herein, we chemically modified oridonin and generated a series of novel analogues. We then employed MTT assay to detect their effects on cell growth and a number of new and potent molecules have been identified. Among them, compounds CYD-6-86 and CYD-6-92 significantly inhibited the proliferation of human breast cancer MDA-MB-231 and MCF-7 cells. Furthermore, both compounds induced enhanced apoptosis in a dose- and time-dependent fashion when compared with oridonin. Cell cycle analysis indicated that both CYD-6-86 and CYD-6-92 induced S phase arrest in MDA-MB-231 cells and G0/G1 phase arrest in MCF-7 cells, while oridonin induced G2/M phase arrest in MDA-MB-231 and MCF-7 cells. Consistent with oridonin, Western blot analysis showed that CYD-6-86 and CYD-6-92 inhibited the expression of NF-κB and Bcl-2, and increased expression of Bax and cleaved PARP. Intriguingly, compounds CYD-6-86 and CYD-6-92 have demonstrated to suppress the growth of adriamycin-resistant MCF-7 clone, while at the same dosage oridonin displayed no effect on these cells. Our findings suggest that these new analogues may be superior to the natural product oridonin to overcome the chemo-resistance, and have great potential to be developed as novel therapeutics for the treatment of breast cancer. Citation Format: Yusong Zhang, Chunyong Ding, Zhengduo Yang, Haijun Chen, Lili Chu, Jia Zhou, Qiang Shen. Discovery of potent oridonin derivatives for the treatment of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5573. doi:10.1158/1538-7445.AM2013-5573