How would you describe the effect of artesunate on levels of genes that control ferroptosis? What is the exact (if known) mechanism of ART/ART derivatives on inducing ferroptosis in cancer cells?
Ferroptosis produced by artesunate and it's derivatives does not seem to act at the level of the gene. It seems to be related to the accumulation of ROS and an oxidative stress. Iron is a necessary auxiliary in the process but can be replaced by cadmium.
Artesunate blocks detoxification pathways probably by blocking the xCT exchanger that extrudes glutamate and imports cystine. Cystine is one of the building blocks of cysteine to form glutathion.
Tomas Koltai So you're thinking ART will not alter GPX4 activity nor alter levels of iron-regulating proteins (i.e, ferroportin, transferrin, ferritin)? I am curious in what way iron egress takes a role when ferroptosis occurs; would cancer cells try to maintain homeostasis by increasing iron egress to reduce Fenton Reaction? I think a lot on ART and iron homeostasis on ferroptosis still remains elusive, which makes it difficult to make educated assumptions/hypotheses.
I appreciate your response. It helps me. Thank you
I do not know if artesunate alters GPX4 activity. What I do know is that Fe is not the main actor in ferroptosis. It can be replaced by other metals. The action of metals in ferroptosis is that they act as electron acceptor and intervene in the redox process. Ferroptosis is an oxidative stress in which metals increase the process but are not determinant for the process itself.
Actually any inhibitor of the xCT channel is able to produce ferroptosis. Iron chelation impedes this process because iron chelation decreases the oxidative stress.
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