Overview of Ferroptosis and Synthetic Lethality Strategies

Abstract

Ferroptosis, a term first proposed in 2012, is iron-dependent, non-apoptotic regulatory cell death induced by erastin. Ferroptosis was originally discovered during synthetic lethal screening for drugs sensitive to RAS mutant cells, and is closely related to synthetic lethality. Ferroptosis sensitizes cancer stem cells and tumors that undergo epithelial−mesenchymal transition and are resistant to anticancer drugs or targeted therapy. Therefore, ferroptosis-inducing molecules are attractive new research targets. In contrast, synthetic lethal strategies approach mechanisms and genetic abnormalities that cannot be directly targeted by conventional therapeutic strategies, such as RAS mutations, hypoxia, and abnormalities in the metabolic environment. They also target the environment and conditions specific to malignant cells, have a low toxicity to normal cells, and can be used in combination with known drugs to produce new ones. However, the concept of synthetic lethality has not been widely adopted with ferroptosis. In this review, we surveyed the literature on ferroptosis-related factors and synthetic lethality to examine the potential therapeutic targets in ferroptosis-related molecules, focusing on factors related to synthetic lethality, discovery methods, clinical application stages, and issues in drug discovery.

NFE2L1-mediated proteasome function protects from ferroptosis

“…Furthermore, we show that bortezomib by itself does not cause ferroptotic cell death, but careful titration of proteasome inhibition accelerates ferroptosis in human patient-derived GPX4-mutated cells. This finding may open possibilities for combined therapy with inducers of ferroptosis [34] and proteasomal inhibition, as they do not only have additional toxicity but rather synergistic potential.…”

NFE2L1-mediated proteasome function protects from ferroptosis

“…On the other hand, proteasomal inhibitors such as bortezomib are already in clinical use in the therapy against multiple myeloma. Clinical trials with the erastin analogue PLRX 9393 ( ClinicalTrials.gov Identifier: NCT01695590 ) were carried out for the same disease but so far remained inconclusive [ 34 ]. Our data support the notion that the route of ferroptosis has differential effects on NFE2L1 and UPS, which highlight the need for more studies in this context.…”

“…Furthermore, we show that bortezomib by itself does not cause ferroptotic cell death, but careful titration of proteasome inhibition accelerates ferroptosis in human patient-derived GPX4-mutated cells. This finding may open possibilities for combined therapy with inducers of ferroptosis [ 34 ] and proteasomal inhibition, as they do not merely have additional toxicity but rather synergistic potential as well.…”

Hydrogen Sulfide Biology and Its Role in Cancer

“…A novel non-apoptotic cell death mechanism mediated through an iron-dependent lipid peroxidation damage was called “ferroptosis” in 2012 [ 208 ]. Ferroptosis is a type of cell death that is caused by cell membrane damage, via glutathione peroxidase (GPX) activity failure and intracellular lipid peroxide, which is accompanied by iron-dependent reactive oxygen species production (ROS) [ 208 , 209 ]. Its physiology, genetics, and biochemical properties are distinct from apoptosis, necrosis, autophagy, and pyroptosis [ 210 ].…”