Abstract 5384: Cell growth of sunitinib-resistant renal cell carcinoma was inhibited by Shikonin through necroptosis induction and Akt/mTOR signaling inhibition

Abstract Despite the establishment of new therapy options during the last decades, advanced renal cell carcinoma (RCC) remains an uncurable disease, due to evolving drug-resistance. New, more efficient treatment strategies are still in urgent demand. Shikonin (SHI) from Traditional Chinese Medicine has exhibited anti-tumor properties in several tumor entities. Thus, in the current investigation we evaluated the impact of SHI on progressive growth and metastatic behavior, not only in therapy-sensitive (parental) but also in therapy-resistant RCC cells. Parental and sunitinib-resistant RCC cells, Caki-1, 786-O, KTCTL-26, and A498, were treated with SHI. Tumor cell growth, proliferation, clonogenic capacity, cell cycle phase distribution, induction of cell death (apoptosis and necroptosis) and the expression and activity of regulating and signaling proteins were evaluated. Moreover, the adhesion and chemotactic activity of the RCC cells after exposure to SHI were investigated. SHI did not affect cell motility but led to significant inhibition of progressive tumor cell growth in both therapy-sensitive and therapy-resistant RCC cells. Thereby, SHI significantly inhibited the growth, proliferation and clone formation in parental and sunitinib-resistant RCC cells by G2/M phase arrest through down-regulation of cell cycle activating proteins, blocking cell division. Furthermore, SHI induced apoptosis and necroptosis by activating necrosome complex proteins. Concomitantly, SHI impaired the Akt/mTOR pathway, pivotal for cell survival and growth. Thus, SHI may hold promise as an additive option in treating patients with advanced and therapy-resistant RCC. Citation Format: Eva Juengel, Sascha D. Markowitsch, Olesya Vakhrusheva, Yasminn Akele, Jovanna Kitanovic, Patricia Schupp, Kimberly S. Slade, Anita Thomas, Igor Tsaur, Rene Mager, Thomas Efferth, Axel Haferkamp. Cell growth of sunitinib-resistant renal cell carcinoma was inhibited by Shikonin through necroptosis induction and Akt/mTOR signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5384.