Abstract
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.
Highlights
The use of medications is often limited by “off target” adverse events that frequently involve the mitochondria [1]
Regorafenib may produce fatal hepatotoxicity, a complication that has not been linked to sorafenib [6,7]
This study employed structural and functional surrogate biomarkers to investigate the toxic effects of sorafenib and regorafenib in vitro
Summary
The use of medications is often limited by “off target” adverse events that frequently involve the mitochondria [1]. Intracellular caspase activity Liver specimens were incubated at 37°C in oxygenated KH buffer containing 37 μM Ac-DEVD-AMC with and without 32 μM zVADfmk (final volume, 0.5 mL). For tissue treated with sorafenib, the hepatocyte showed mild swelling of the mitochondria and relatively preserved rER.
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