Ex vivo Effects of Sorafenib and Regorafenib on Murine Hepatocytes
- *Corresponding Author:
- Abdul-Kader Souid
Departments of Pediatrics, UAE University
Al-Ain, Abu Dhabi, United Arab Emirates
E-mail: [email protected]
Received Date: May 22, 2014; Accepted Date: July 09, 2014; Published Date: July 14, 2014
Citation: Souid A, Almarzooqi S, Albawardi A, Shaban S, Al-Dabbagh B, et al. (2014) Ex vivo Effects of Sorafenib and Regorafenib on Murine Hepatocytes. J Clin Toxicol 4:207. doi: 10.4172/2161-0495.1000207
Copyright: © 2014, Souid A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sorafenib and regorafenib are structurally-related small-molecular-weight inhibitors of cellular kinases. Regorafenib has a Boxed Warning stating: “Severe and sometimes fatal hepatotoxicity has been observed in clinical trials”, while sorafenib is considered less hepatotoxic. This ex vivo study assessed the effects of sorafenib (2.5 and 50 μM) and regorafenib (5.0 and 50 μM) on liver structure, ultrastructure, cellular respiration (mitochondrial O2 consumption), ATP, caspase activity, urea synthesis, and glutathione. Liver fragments from Taylor Outbred mice were incubated in Krebs-Henseleit buffer (continuously gassed with 95% O2:5% CO2) with and without the drugs for 3 to 4 h. The presence of sorafenib or regorafenib had insignificant effects on liver structure, cellular respiration, ATP, caspase-3 activity, urea synthesis, and glutathione. At 3 h, liver histology with and without 2.5 μM sorafenib or 5.0 μM regorafenib was similar. Liver histology with 50 μM sorafenib was slightly worse than untreated tissue at 3 h, showing single hepatocyte necrosis and cellular disintegration. With 50 μM regorafenib, the histology was closely mirroring untreated tissue at 3 h. Similarly, caspase-3, caspase-9, cytochrome c, BAX and annexin A2 immunostains showed no significant drug effects at 4 h (2.5 μM sorafenib or 5.0 μM regorafenib). Electron microscopy revealed a more prominent loss of rough endoplasmic reticulum (rER) integrity with regorafenib treatment compared with sorafenib treatment. Thus, derangements in the rER were more prominent with regorafenib. Otherwise, the studied hepatic surrogate biomarkers did not distinguish between the two compounds.