Ferroptosis has become a promising target for cancer therapy. This regulated non-apoptotic cell death process is described as an iron-dependent lipid peroxidation, specifically necessitating peroxidation of polyunsaturated fatty acid-containing phospholipids. The protective mechanism in healthy cells is for the resulting lipid hydroperoxides to be converted to the corresponding lipid alcohols by glutathione peroxidase 4 (GPX4) and that being able to target this enzyme for inhibition in cancer cells could overcome the suppression of ferroptosis.
A collaboration between groups at AbbVie, Inc. and Stanford University, led by Relja Popovic and Scott J. Dixon respectively, explored the scope for GPX4 therapeutically.
In the course of the studies a sensor of lipid peroxidation (Bodipy 581/591 C11) and DRAQ7 were used in combination to demonstrate that cells undergoing ferroptosis accumulate lipid peroxides and subsequently die, and that this could be modulated under different conditions.
What became clear with the complex investigations by the authors was that the transition from 2-D to 3-D cell culture system reduced the sensitivity of cells to GPX4 inhibition - due to a substitution by monounsaturated fatty acids in the 3D culture from the upregulation of another enzyme (SCD). Under this 3-D culture condition, it is generally understood to recapitulate better the in vivo condition, though for this case needs to be seen as initial findings and requires further investigation.
GPX4 remains limited in its promise as a target to block suppression of ferroptosis due to these confounding data and without the means currently to specifically target cancer cell GPX4 based on another feature e.g. proliferation rate, tumour cell surface marker, etc.
Reference:
https://doi.org/10.1158/0008-5472.CAN-24-4207
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