Metal Complexes or Chelators with ROS Regulation Capacity: Promising Candidates for Cancer Treatment

Abstract

Reactive oxygen species (ROS) are rapidly eliminated and reproduced in organisms, and they always play important roles in various biological functions and abnormal pathological processes. Evaluated ROS have frequently been observed in various cancers to activate multiple pro-tumorigenic signaling pathways and induce the survival and proliferation of cancer cells. Hydrogen peroxide (H₂O₂) and superoxide anion (O₂^•-) are the most important redox signaling agents in cancer cells, the homeostasis of which is maintained by dozens of growth factors, cytokines, and antioxidant enzymes. Therefore, antioxidant enzymes tend to have higher activity levels to maintain the homeostasis of ROS in cancer cells. Effective intervention in the ROS homeostasis of cancer cells by chelating agents or metal complexes has already developed into an important anti-cancer strategy. We can inhibit the activity of antioxidant enzymes using chelators or metal complexes; on the other hand, we can also use metal complexes to directly regulate the level of ROS in cancer cells via mitochondria. In this review, metal complexes or chelators with ROS regulation capacity and with anti-cancer applications are collectively and comprehensively analyzed, which is beneficial for the development of the next generation of inorganic anti-cancer drugs based on ROS regulation. We expect that this review will provide a new perspective to develop novel inorganic reagents for killing cancer cells and, further, as candidates or clinical drugs.

Keywords: SOD1; TrxR; anti-cancer; antioxidant enzymes; chelators; metal complexes; mitochondria; reactive oxygen species.

Figure 1

ROS in cancer cells. (A) Generation and chemical structures of ROS. (B) Brief metabolic process and signal regulation of intracellular ROS. (C) Balancing ROS generation and scavenging in cancer cells to remain in the tumorigenic range.

Figure 2

Summary of SOD1 inhibitors based on copper chelation. The specific activity inhibition of SOD1 selectively kills cancer cells by regulating the intracellular ROS signaling network.

Figure 3

Summary of metal complexes inhibiting TrxR and CAT. (A) Structures of anti-cancer metal complexes for TrxR inhibition to regulate intracellular ROS levels. (B) Structures of metal complexes for CAT inhibition.

Figure 4

Summary of metal complexes activating ROS-mediated signaling by mitochondrial dysfunction.