Abstract
Simple SummaryAdvanced 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.
Highlights
Renal cell carcinoma (RCC) is the most common cancer of the kidney, accounting for80–90% of kidney cancer, and is the most aggressive urologic cancer [1–3]
We have shown in previous investigations that the expression and activity of AKT increases with the emergence of therapy resistance in renal cell carcinoma (RCC) in vitro and in vivo [31–33]
Parental and sunitinib-resistant Caki-1 cells showed a higher sensitivity to SHI than the other RCC cells, with IC50 values of 0.58 μM and 0.82 μM, respectively
Summary
Renal cell carcinoma (RCC) is the most common cancer of the kidney, accounting for80–90% of kidney cancer, and is the most aggressive urologic cancer [1–3]. RCC is often initially asymptomatic, resulting in late diagnosis, and approximately 25–30% of patients have distant metastases at initial diagnosis [7]. Another 15–30% of patients develop metastases during therapy. Sunitinib is a TKI that has contributed to significant improvement in the treatment of patients with advanced RCC, in first-line therapy [8]. This treatment leads only to disease stabilization in terms of prolongation of progression-free and overall survival [7]. Despite the benefits of targeted therapies for patients with metastatic (advanced) RCC, the long-term prognosis remains poor, with a 5-year survival rate of 17% [9]. Resistance to established therapeutics is mainly responsible for this poor outcome [10,11]
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