Oncotarget

Research Papers:

Orellanine specifically targets renal clear cell carcinoma

Lisa Buvall, Heidi Hedman, Alina Khramova, Deman Najar, Lovisa Bergwall, Kerstin Ebefors, Carina Sihlbom, Sven Lundstam, Anders Herrmann, Hanna Wallentin, Emelie Roos, Ulf A. Nilsson, Martin Johansson, Jan Törnell, Börje Haraldsson and Jenny Nyström _

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Oncotarget. 2017; 8:91085-91098. https://doi.org/10.18632/oncotarget.19555

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Abstract

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

Correspondence to:

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

ABSTRACT

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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