Ferroptosis in Neurons and Cancer Cells Is Similar But Differentially Regulated by Histone Deacetylase Inhibitors

Area of Science:

• Biochemistry
• Oncology
• Neuroscience

Background:

• Ferroptotic death is a tumor suppression mechanism triggered by X_c^- transporter inhibitors, leading to glutathione depletion and lipid peroxidation-driven cell death.
• X_c^- transporter inhibitors can cause neuronal cell death, raising concerns about neurotoxicity during chemotherapy.
• Identifying agents that selectively protect neurons while enhancing ferroptosis in tumors is crucial for therapeutic development.

Purpose of the Study:

• To investigate agents that can selectively protect neurons from ferroptosis while exacerbating it in cancer cells.
• To identify novel therapeutic strategies for cancer treatment that minimize neurotoxicity.

Main Methods:

• Comparing ferroptotic death induction by erastin in HT1080 fibrosarcoma cells and primary cortical neurons.
• Evaluating the effects of known ferroptosis inhibitors and class I histone deacetylase (HDAC) inhibitors on neuronal and cancer cell ferroptosis.
• Analyzing the cell death pathways induced by erastin and oxidative glutamate toxicity.

Main Results:

• Ferroptotic death induced by erastin occurred in both fibrosarcoma cells and neurons, but was more potent in cancer cells.
• Class I HDAC inhibitors selectively protected neurons from ferroptosis while enhancing it in fibrosarcoma cells.
• Cell death pathways induced by erastin in neurons and cancer cells were statistically identical to each other and to oxidative glutamate toxicity.

Conclusions:

• Class I HDAC inhibitors represent a novel class of agents for augmenting tumor suppression via ferroptosis induction.
• HDAC inhibitors can minimize neuronal toxicity associated with ferroptosis-inducing chemotherapy, potentially reducing peripheral neuropathy and chemo brain.
• This study identifies a promising therapeutic avenue for enhancing cancer treatment efficacy and patient safety.