Shikonin Inhibits Cell Growth of Sunitinib-Resistant Renal Cell Carcinoma by Activating the Necrosome Complex and Inhibiting the AKT/mTOR Signaling Pathway

Simple Summary Advanced renal cell carcinoma (RCC) remains an incurable disease, despite the establishment of new therapeutic options during the last decades. Unfortunately, drug resistance inevitably evolves, making better treatment strategies essential. Shikonin (SHI) from traditional Chinese medicine has shown promising antitumor properties with other tumor entities. Thus, in the current investigation, we evaluated the impact of SHI on therapy-sensitive and therapy-resistant RCC cells. SHI led to significant inhibition of progressive tumor cell growth in both therapy-sensitive and therapy-resistant RCC cells. This was accompanied by cell cycle arrest and reduction in cell cycle activating proteins, which results in blockage of cell division. SHI also activated necrosome complex proteins, leading to necroptosis, a programmed cell death. Furthermore, SHI inhibited the AKT/mTOR pathway, pivotal for cell survival and growth. Thus, SHI may hold promise in improving the treatment of RCC, even in its advanced form. Therapy resistance remains a major challenge in treating advanced renal cell carcinoma (RCC), making more effective treatment strategies crucial. Shikonin (SHI) from traditional Chinese medicine has exhibited antitumor properties in several tumor entities. We, therefore, currently investigated SHI's impact on progressive growth and metastatic behavior in therapy-sensitive (parental) and therapy-resistant Caki-1, 786-O, KTCTL-26, and A498 RCC cells. 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 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. Furthermore, SHI induced apoptosis and necroptosis by activating necrosome complex proteins. Concomitantly, SHI impaired the AKT/mTOR pathway. Adhesion and motility were cell line specifically affected by SHI. Thus, SHI may hold promise as an additive option in treating patients with advanced and therapy-resistant RCC.

Automated summary

This study evaluated the impact of shikonin (SHI) from traditional Chinese medicine on therapy-sensitive and therapy-resistant renal cell carcinoma (RCC) cells. The results showed that SHI could inhibit the growth of RCC cells and block cell division. SHI also induced cell death and inhibited a key pathway for cell survival and growth. Therefore, SHI may be a potential option for treating RCC.