Chemotherapy is one of the most widely used treatments for cancer. In this approach, patients are given cytotoxic agents that ideally accumulate in tumor tissue and kill cancer cells. Platinum-based drugs are among the most commonly used chemotherapeutic agents worldwide. Despite their clinical success, their use is limited by severe side effects, including kidney damage, nausea, vomiting, and bone marrow suppression, as well as low selectivity for cancer cells. Moreover, the emergence of platinum-resistant tumors poses a growing challenge. Consequently, researchers are actively exploring new compounds with alternative mechanisms of action.

In our research group, we focus on the design, synthesis, and biological evaluation of Cu(II) complexes as potential anticancer agents (Figure 1). Cu(II) complexes have redox properties within the biological range, allowing them to undergo redox cycling in cancer cells and catalytically generate cytotoxic species. Importantly, these compounds are two orders of magnitude more cytotoxic than commonly used platinum drugs, meaning only small amounts are needed to achieve a therapeutic effect.

Figure 1. Structure of redox-active Cu(II) complex as a chemotherapeutic agent.

Using specific fluorescent probes, we can monitor the production of hydroxyl radicals in living cells via fluorescence microscopy. Further studies revealed that the compounds accumulate in the mitochondria of cancer cells, causing depolarization of the mitochondrial membrane potential. Mechanistic studies indicated that cell death is induced by cuproptosis, a recently discovered and highly promising form of cell death. Cuproptosis is associated with the oligomerization of the protein dihydrolipoamide S-acetyltransferase (DLAT) (Figure 2). Based on this unique mechanism of action, these compound are able to overcome drug resistances associated with other chemotherapeutic drugs.

Figure 2. Confocal microscopy image of cancer cells upon incubation with the nucleus specific dye DAPI, the mitochondria specific dye MitoTracker Deep Red, and the DLAT antibody for verification of the cuproptosis mechanism. 

Encouraged by these results in two-dimensional monolayer cancer cells, we further tested the compounds in three-dimensional multicellular tumor spheroids, a widely accepted model that better replicates the microenvironment of solid tumors. The compounds effectively disrupted the three-dimensional structure of the spheroids at nanomolar concentrations (Figure 3).

Figure 3. Light microscopy images of three-dimensional multicellular tumor spheroids upon treatment with cisplatin or Cu(II) complex as a chemotherapeutic agent.

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