Orellanine specifically targets renal clear cell carcinoma
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Lisa Buvall1,*, Heidi Hedman2,*, Alina Khramova1, Deman Najar1, Lovisa Bergwall1, Kerstin Ebefors1, Carina Sihlbom6, Sven Lundstam3, Anders Herrmann4, Hanna Wallentin1, Emelie Roos1, Ulf A. Nilsson2, Martin Johansson5, Jan Törnell1, Börje Haraldsson1 and Jenny Nyström1
1Institute of Neuroscience and Physiology, Gothenburg, Sweden
2Institute of Medicine, Gothenburg, Sweden
3Institute of Clinical Sciences at University of Gothenburg, Gothenburg, Sweden
4National Food Agency, Uppsala, Sweden
5Department of Laboratory Medicine, Pathology, Lund University, Malmö, Sweden
6Proteomics Core Facility at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
*These authors contributed equally to this work
Jenny Nyström, email: Jenny.Nystrom@gu.se
Keywords: clear cell renal cell carcinoma, nephrotoxin, anti-carcinogenic treatment, apoptosis, necrosis
Received: May 13, 2017 Accepted: July 11, 2017 Published: July 25, 2017
Renal cell carcinoma (RCC), arising from the proximal tubule in the kidney, accounts for approximately 85% of kidney cancers and causes over 140,000 annual deaths worldwide. In the last decade, several new therapies have been identified for treatment of metastatic RCC. Although these therapies increase survival time compared to standard care, none of them has curative properties. The nephrotoxin orellanine specifically targets proximal tubular epithelial cells, leaving other organs unaffected. We therefore hypothesized that the selective toxicity of orellanine extends to clear cell RCC (ccRCC) cells since they emanate from proximal tubular cells. Orellanine would thus target both primary and metastatic ccRCC in vitro and in vivo. We found that orellanine induces dose-dependent cell death in proximal tubular cells and in all ccRCC cells tested, both primary and cell lines, with no toxicity detected in control cells. The toxic action of orellanine involve decreased protein synthesis, disrupted cell metabolism and induction of apoptosis. In nude rats carrying human ccRCC xenografts, brief orellanine treatment eliminated more than 90% of viable tumor mass compared to control rats.
This identifies orellanine as a potential treatment concept for ccRCC patients on dialysis, due to its unique selective toxicity towards ccRCC.
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