A New Oridonin Analogue Suppresses Triple‐Negative Breast Cancer Cells and Tumor Growth via Inducing the Expression of Death Receptor 5

Abstract

Triple‐negative breast cancer (TNBC) remains the leading cause of death among women with breast cancer worldwide. Oridonin is a natural anti‐cancer compound isolated from the traditional Chinese herb Rabdosia rubescens. However, the antitumor efficacy of oridonin for TNBC and other cancers is far away from ideal. In this study, we investigated a series of newly designed oridonin analogues against HCC1806 and HCC1937 TNBC cell lines and identified CYD‐6‐28 that significantly inhibits cancer cell proliferation, induces G2/M phase cell cycle arrests and apoptosis. CYD‐6‐28 induces the expression of p21 and the cleavage of caspase‐8, −3, −7 and PARP, and inhibits the expression of Cyclin D1, FLIP and XIAP. CYD‐6‐28 also inhibits the activation of STAT3 and AKT while inducing the activation of ERK. We demonstrated that CYD‐6‐28 induces apoptosis at least partially through inducing the expression of Death Receptor 5 (DR5). Finally, CYD‐6‐28 significantly suppresses HCC1806 xenograft tumor growth in nude mice at 5 mg/kg without significant toxicity. Taken together, CYD‐6‐28 has the potential to be developed as a promising therapeutic agent to treat TNBC.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (81120108019, U1132605, and 81325016 to Chen, C), and the grants P30 DA028821 and R01 DA038446 from the National Institutes of Health, and Cancer Prevention Research Institute of Texas (CPRIT) award (to Zhou, J).