Exploring the Use of Intracellular Chelation and Non-Iron Metals to Program Ferroptosis for Anticancer Application

Abstract

The discovery of regulated cell death (RCD) revolutionized chemotherapy. With caspase-dependent apoptosis initially being thought to be the only form of RCD, many drug development strategies aimed to synthesize compounds that turn on this kind of cell death. While yielding a variety of drugs, this approach is limited, given the acquired resistance of cancers to these drugs and the lack of specificity of the drugs for targeting cancer cells alone. The discovery of non-apoptotic forms of RCD is leading to new avenues for drug design. Evidence shows that ferroptosis, a relatively recently discovered iron-based cell death pathway, has therapeutic potential for anticancer application. Recent studies point to the interrelationship between iron and other essential metals, copper and zinc, and the disturbance of their respective homeostasis as critical to the onset of ferroptosis. Other studies reveal that several coordination complexes of non-iron metals have the capacity to induce ferroptosis. This collective knowledge will be assessed to determine how chelation approaches and coordination chemistry can be engineered to program ferroptosis in chemotherapy.

Keywords: chelation; ferroptosis; noniron metal complexes; regulated cell death.

Figure 1.

Timeline of ferroptosis-related findings [–14] (image created using Biorender.com).

Figure 2.

Three major routes of ferroptosis onset related to the metabolism of iron, antioxidants, and lipids (image created using Biorender.com).

Figure 3.

Representative iron coordination within rubredoxin (A), hemoglobin (B), human transferrin (C), and ferrocene (D).

Figure 4.

Triapine and a selection of its physiologically relevant metal compound species. At a near neutral pH of 7.4, Fe(II/III) forms the (A) modality, Cu(II) forms the (B) modality, and Zn(II) forms a mixture of the (A) and (B) modalities.

Figure 5.

The Zn(II) binding site within human carbonic anhydrase II, demonstrating a tetrahedral coordination.

Figure 6.

Human ceruloplasmin type 1 copper coordination. It is important to note that ceruloplasmin has six Cu binding sites, of which three are type 1 [30].

Figure 7.

Proposed mechanisms of ferroptosis induction through copper depletion and overload (image created using Biorender.com).

Figure 8.

Cu(II) complexes of bathocuproynedisulfonic acid (A), elesclomol (B), and diethyldithiocarbamate (C).

Figure 9.

The Zn(II)-5-Fu metallodrug network (Zn-Fu MN) [65].

Figure 10.

Proposed mechanisms of ZnO-NP’s induction of ferroptosis (image created using Biorender.com).

Figure 11.

Proposed mechanisms of cisplatin’s induction of apoptosis and ferroptosis (image created using Biorender.com).

Figure 12.

Proposed mechanism of oxaliplatin’s induction of apoptosis and ferroptosis (image created using Biorender.com) [89].

Figure 13.

Proposed mechanism of auranofin’s induction of apoptosis and ferroptosis (image created using Biorender.com).

Figure 14.

Proposed mechanism of IrL1 and MitoIrL2’s induction of apoptosis and ferroptosis (image created using Biorender.com) [107].

Figure 15.

Proposed mechanism of Os2’s induction of ferroptosis (image created using Biorender.com) [108].