Abstract 1423: Shikonin impairs the growth of docetaxel-resistant prostate cancer cells by necroptosis

Abstract

Introduction: Prostate carcinoma (PCa) is the most common malignancy in men. Androgen-targeted therapy and chemotherapy are currently the treatment of choice for advanced stages. Due to resistance towards these therapies, prognosis remains poor and new treatment options are urgently required. Shikonin (SHI) from Traditional Chinese Medicine (TCM) might be promising, since it induces anti-tumor effects in different tumor entities. However, data on PCa are few, and data on resistant PCa are not existent. Material and Methods: Parental (=sensitive) and docetaxel-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1 - 1.5 μM] for 24, 48, or 72 hours. Untreated cells served as controls. Tumor cell growth, proliferation, cell cycle, and the expression of cell cycle regulating proteins were assessed. Several cell deaths, like apoptosis, necrosis and necroptosis as well as the metabolic activity were evaluated. Results: Time- and dose-dependent exposure to SHI significantly reduced tumor cell growth and proliferation in parental and docetaxel-resistant PCa cells, compared to the untreated controls. This was accompanied by cell cycle arrest in the G2/M phase in parental PC3 and docetaxel-resistant DU145 and S phase arrest in resistant 22Rv1, associated with modulated expression of cell cycle regulating proteins. Significant apoptotic effects were observed in parental and docetaxel-resistant PC3, DU145, 22Rv1, and resistant LNCaP. Moreover, SHI induced necroptosis in all parental and resistant PCa cells, as shown by additional application to the necroptosis inhibitor necrostatin-1. In line with this, RIP-1 expression enhanced under SHI exposure. In contrast, SHI did not alter the metabolic activity of the PCa cells. Conclusion: Significant anti-tumor effects are apparent in parental but also in docetaxel-resistant PCa cells after SHI application. Thus, adding SHI to standard therapies might be a promising treatment strategy for patients with advanced prostate cancer. Further investigations are necessary to verify our findings. Funding: Friedrich-Spicker-Stiftung (2017). Acknowledgments: The main portion of the results presented here are part of the MD thesis of Kira M. Juetter at the Department of Urology and Pediatric Urology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. Citation Format: Sascha D. Markowitsch, Kira M. Juetter, Patricia Schupp, Kristine Hausschulte, Olesya Vakhrusheva, Jindrich Cinatl, Martin Michaelis, Thomas Efferth, Axel Haferkamp, Eva Juengel. Shikonin impairs the growth of docetaxel-resistant prostate cancer cells by necroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1423.