Abstract P6-03-19: Oridonalogs reverse chemoresistance in breast cancer cells by targeting STAT3

Abstract

Abstract Chemotherapy remains the mainstream treatment option for invasive and metastatic breast cancer. Adriamycin (ADR) is one of the most frequently used and an effective chemotherapeutic agent for treating patients with breast cancer. However, the resistance towards ADR becomes a major obstacle to achieve efficacy and favorable outcomes in breast cancer patients with chemotherapy. We recently developed a serial oridonalogs that may possess the ability to overcome chemoresistance in cancer cells, whereas whether these novel anti-cancer agents reverse ADR resistance in resistant breast cancer cells are not adequately explored and further the mechanism of action has not been studied. In this study, oridonalogs, YD0514, CYD0618, and CYD0686, were used to determine their effects on the proliferation of the ADR-resistant breast cancer cells. We found significant inhibition of proliferation of wild-type breast cancer cell line MCF-7 and ADR-resistant MCF-7/ADR cells, time- and dose-dependently. Among the tested compounds, CYD0618 and CYD0686 were more effective in inducing apoptosis in wild-type and resistant breast cancer cells than YD0514, in comparison to the natural product and lead compound oridonin. In addition, total STAT3 level was found higher in ADR-resistant breast cancer cells, while phospho-STAT3 was higher in resistant cells. CYD0618 inhibited STAT3 activation in ADR-resistant cells. Our findings suggest that STAT3 activation may be critically involved in the development of acquired resistance to ADR, while oridonalogs such as CYD0618 may open the avenue to reverse and overcome ADR resistance in breast cancer by targeting STAT3. Further mechanistic explorations are currently underway. Citation Format: Xi Liu, Yefei Wen, Hyejin Kim, Pingyuan Wang, Haiying Chen, Mingdao Hu, Ye Ding, Jia Zhou, Qiang Shen. Oridonalogs reverse chemoresistance in breast cancer cells by targeting STAT3 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-19.