Novel chelators for cancer treatment: where are we now?

Abstract

Significance: Under normal circumstances, cellular iron levels are tightly regulated due to the potential toxic effects of this metal ion. There is evidence that tumors possess altered iron homeostasis, which is mediated by the perturbed expression of iron-related proteins, for example, transferrin receptor 1, ferritin and ferroportin 1. The de-regulation of iron homeostasis in cancer cells reveals a particular vulnerability to iron-depletion using iron chelators. In this review, we examine the absorption of iron from the gut; its transport, metabolism, and homeostasis in mammals; and the molecular pathways involved. Additionally, evidence for alterations in iron processing in cancer are described along with the perturbations in other biologically important transition metal ions, for example, copper(II) and zinc(II). These changes can be therapeutically manipulated by the use of novel chelators that have recently been shown to be highly effective in terms of inhibiting tumor growth.

Recent advances: Such chelators include those of the thiosemicarbazone class that were originally thought to target only ribonucleotide reductase, but are now known to have multiple effects, including the generation of cytotoxic radicals.

Critical issues: Several chelators have shown marked anti-tumor activity in vivo against a variety of solid tumors. An important aspect is the toxicology and the efficacy of these agents in clinical trials.

Future directions: As part of the process of the clinical assessment of the new chelators, an extensive toxicological assessment in multiple animal models is essential for designing appropriate dosing protocols in humans.