Ferroptosis in neurons and cancer cells is similar but differentially regulated by histone deacetylase inhibitors

Abstract

Ferroptotic death is a mechanism for tumor suppression by pharmacological inhibitors that target the X_c^- transporter (cystine/glutamate antiporter) in a host of non-CNS and CNS tumors. Inhibition of this transporter leads to reduction of cystine uptake, cyst(e)ine deprivation, subsequent depletion of the versatile antioxidant glutathione, and reactive lipid species dependent death. Accordingly, pharmacological inhibitors of the X_c^- transporter can also induce neuronal cell death raising concerns about toxicity in the CNS and PNS if these agents are used for chemotherapy. Here, we show that ferroptotic death induced by the canonical ferroptosis inducer erastin is similar in HT1080 fibrosarcoma cells and primary cortical neurons although cell death is mediated more potently in cancer cells. Reducing the toxicity of ferroptosis inducers will require, among other things, the identification of agents that protect neurons from ferroptosis but exacerbate it in tumor cells. While we show that a number of agents known to block ferroptosis in primary mouse neurons also inhibit ferroptosis in fibrosarcoma cells, class I histone deacetylase (HDAC) inhibitors selectively protect neurons while augmenting ferroptosis in cancer cells. Our results further suggest that cell death pathways induced by erastin in these two cell types is statistically identical to each other and identical to oxidative glutamate toxicity in neurons, where death is also mediated via inhibition of X_c^- cystine transport. Together, these studies identify HDACs inhibitors as a novel class of agents to augment tumor suppression by ferroptosis induction and to minimize neuronal toxicity that could manifest as peripheral neuropathy or chemo brain.

Significance Statement A major challenge in cancer chemotherapy is to effectively kill tumor cells while preserving healthy issue. The nervous system is particularly vulnerable to side effects by anti-cancer agents. Agents that induce a recently identified type of cell death, called ferroptosis, are widely being considered for cancer treatment. However, precise understanding of how ferroptosis induction in cancer cells may simultaneously thwart function or viability of post-mitotic neurons is essential in defining the efficacy and toxicity of these agents. We show that mechanisms of ferroptotic cell death in cancer cells are similar to those in neurons. We leverage prior studies of ferroptosis in neurons to identify histone deacetylase inhibitors as agents that enhance chemotherapy-induced ferroptosis of tumors while inhibiting ferroptosis in neurons.