From iron chelation to overload as a therapeutic strategy to induce ferroptosis in hematologic malignancies

Figures & data

Table 1. Features of different kinds of RCD.

Types	Morphology	Biochemistry	Genetics
Ferroptosis	Shrunken mitochondria, condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista	Iron accumulation and lipid peroxidation	TFR1, FTH1, FTL GPX4, SLC7A11, SLC3A2, VDAC2/3
Apoptosis	Plasma membrane blebbing; cellular and nuclear volume reduction; nuclear fragmentation, chromatin condensation	Activation of caspases oligonucleosomal DNA fragmentation	Caspase-3, Bcl-2, P53, Bax, Fas
Necrosis	Plasma membrane rupture; organelle swelling; moderate chromatin condensation	Drop in ATP levels; activation of RIP1, RIP3, and MLKL	RIP1, RIP3, MLKL
Pyroptosis	Karyopyknosis, cell edema and membrane rupture	Dependent on caspase-1 and proinflammatory cytokine releases	Caspase-1, IL-1β, IL-18,
Autophagy	Accumulation of double-membraned autophagic vacuoles Nucleus, lack of chromatin condensation	LC3-I to LC3-II conversion Substrate degradation	ATG5, ATG7, Beclin 1

Table 2. Iron chelation strategies in hematological malignancies.

Cancer	Iron chelation strategies	Mechanism	Refs.
Leukemia	DFO	Inhibiting the activity of ribonucleotide reductase;
inhibiting cell viability, inducing cell apoptosis, and regulating expression of apoptosis-related genes.	[27, 28]
	DFO + cytarabine	Increasing iron depletion and apoptosis induced by cytarabine	[29]
	DFO + doxorubicin	Regulating intracellular calcium and increasing sensitivity to doxorubicin.	[30]
	DFX	Inhibiting the NF-κB/ HIF1α pathway and elevating ROS levels;
Inhibition of mTOR signaling by enhancing the expression of REDD1;	[31, 32]
	DFX + decitabine	Increasing apoptosis induced by decitabine	[33]
MDS	DFO/DFX/DFP	Iron deprivation	[34]
DLBCL	Ironomycin	Sequestering iron in the lysosome and to induce cancer cell death	[35]
MM	DFX	Inducing apoptosis by targeting oncogenic Pyk2/β-catenin signaling	[36]
	DFO/DFX	autophagy induced by iron deprivation	[37]

Figure 1. Mechanisms of ferroptosis. The circulated iron (Fe³⁺) combined with transferrin (TF) enters into cells mediated by transferrin receptor (TFR). Fe³⁺ is reduced to Fe²⁺ by iron oxide reductase STEAP3 in the endosome and transported to the cytoplasmic LIP by DMT1. FTH heavy chain is transported to autophagosome after binding with NCOA4, and the degraded iron is released into the cytoplasm. Excessive iron is carried in the extracellular space through FPN. Free iron can also form ROS via the Fenton reaction. System Xc^- (consisting of SLC7A11 and SLC3A2) exports glutamine and imports cystine into the cell. Cystine is then transformed into cysteine for GSH synthesis. ACSL4 catalyzes PUFAs and CoA to synthesize PUFA-CoA, which is then further catalyzed by LPCAT3 into PE-PUFAs. Then LOXs oxidizes PE-PUFAs to PE-PUFAs-OOH. Redox enzymes GPX4 use GSH to reduces the endogenous neutralization of PUFAs-OOH to PUFAs-OH, ultimately reducing ROS accumulation.

Table 3. FINs in hematologic malignancies.

Caner	Inducers	Targeted sites	Refs.
Leukemia	Erastin	HMGB1, iron, VDAC3	[63–65]
	RLS3	GPX4	[66]
	Sorafenib	System Xc^-	[67]
	Artemisinin-type drugs	Iron	[68, 69]
	Nanoparticles	Iron, GSH	[70, 71]
MDS	Erastin	/	[11]
DLBCL	Erastin	System Xc^-	[72]
	RLS3	GPX4	[10]
MM	FTY720	GPX4, SLC7A11	[73]

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