Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib.

TL;DR: The depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib, identifying ferroptosis as an effective mechanism for the induction of cell death in HCC.

Abstract: The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC) In our report, we examined the cytotoxic effects of sorafenib on HCC cells We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors