Novel insights into anticancer mechanisms of elesclomol: More than a prooxidant drug

Abstract

As an essential micronutrient for humans, the metabolism of copper is fine-tuned by evolutionarily conserved homeostatic mechanisms. Copper toxicity occurs when its concentration exceeds a certain threshold, which has been exploited in the development of copper ionophores, such as elesclomol, for anticancer treatment. Elesclomol has garnered recognition as a potent anticancer drug and has been evaluated in numerous clinical trials. However, the mechanisms underlying elesclomol-induced cell death remain obscure. The discovery of cuproptosis, a novel form of cell death triggered by the targeted accumulation of copper in mitochondria, redefines the significance of elesclomol in cancer therapy. Here, we provide an overview of copper homeostasis and its associated pathological disorders, especially copper metabolism in carcinogenesis. We summarize our current knowledge of the tumor suppressive mechanisms of elesclomol, with emphasis on cuproptosis. Finally, we discuss the strategies that may contribute to better application of elesclomol in cancer therapy.

Keywords: Cancer therapy; Copper metabolism; Cuproptosis; Elesclomol; Oxidative stress.

Fig. 1

Overview of systemic and cellular copper homeostasis. The human body primarily absorbs copper through the small intestine, which is then transported to the liver via the bloodstream and excreted into bile. CP serves as the main protein carrier for exchangeable copper in the blood plasma, while excess copper is stored in hepatocytes by MT1 and MT2. At the cellular level, the metal reductase STEAP and the copper transporter CTR1 enable high-affinity copper uptake. Copper is transported to different subcellular organelles through various copper-binding proteins, such as COX17, CCS, and ATOX1. These proteins play a crucial role in ensuring the availability of copper within the cell. Ultimately, ATP7A and ATP7B transfer copper from the cytosol to the TGN lumen. When intracellular copper levels are high, ATP7A and ATP7B exit the TGN, facilitating the efflux of copper from the cell. CP, ceruloplasmin; MT1, metallothionein 1; STEAP, six-transmembrane epithelial antigen of the prostate; CTR1, copper transporter 1; COX17, cytochrome C oxidase copper chaperone 17; CCS, copper chaperone for superoxide dismutase; ATOX1, antioxidant-1; SOD1, superoxide dismutase 1; SCO1, synthesis of cytochrome c oxidase 1; COX11, cytochrome C oxidase copper chaperone 11; CCO, cytochrome C oxidase; ATP7A, ATPase Copper Transporting Alpha; TGN, trans-Golgi network.

Fig. 2

The structure and cellular entry mechanism of elesclomol. Elesclomol forms a 1:1 complex with Cu(II) extracellularly, which rapidly transports copper to mitochondria and releases copper upon reduction to Cu(I) by FDX1. Subsequently, elesclomol-Cu(II) complexes lead to cell death through various mechanisms, including the generation of oxidative stress, targeting metabolically active mitochondria, disruption of iron homeostasis, promoting ferroptosis and inducing cuproptosis. FDX1, ferredoxin 1.

Fig. 3

Cancer cells exhibiting elevated levels of mitochondrial oxidative stress are more sensitive to elesclomol. The effectiveness of elesclomol as an anticancer agent relies on the presence of oxygen, which predominantly fuels cellular energy metabolism through OXPHOS rather than glycolysis. Consequently, targeting glycolysis to enhance mitochondrial respiration may enhance the antitumor efficacy of elesclomol. Blocking the HIF-1α/PDK3 axis by inhibiting the upstream factor NAC1 or utilizing a PDK inhibitor such as DCA can promote oxidative stress and enhance the antitumor efficacy of elesclomol. OXPHOS, oxidative phosphorylation; GLUTs, glucose transporters; LDHA, lactate dehydrogenase A; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinases; DCA, dichloroacetate; HIF1, hypoxia-inducible factor 1; NAC1, nucleus accumbens-1; TCA, tricarboxylic acid; ETC, electron transport chain; ROS, reactive oxygen species.

Fig. 4

Ferroptosis accounts for the anticancer activity of elesclomol. Elesclomol increases Cu(II) levels within the mitochondria and reduces ATP7A expression, resulting in intracellular Cu(II) retention and ROS accumulation. These effects contribute to the degradation of SLC7A11, further amplifying oxidative stress and ultimately triggering ferroptosis in CRC cells. Ub, ubiquitin; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GPX4, glutathione peroxidase 4; CRC: colorectal cancer.

Fig. 5

Schematic diagram of the mechanism of cuproptosis. Elesclomol-induced cuproptosis primarily relies on its direct target FDX1, which catalyzes the reduction of Cu(II) to Cu(I). This reduction event facilitates the lipoylation and aggregation of enzymes, particularly DLAT, involving in the mitochondrial TCA cycle. Additionally, it triggers the loss of Fe–S cluster proteins. These aberrant processes collectively lead to proteotoxic stress and eventual cell death. Importantly, inhibitors targeting ferroptosis (Fer-1), necroptosis (Nec-1), and oxidative stress (NAC) do not affect the occurrence of cuproptosis. DLAT, dihydrolipoamide S-acetyltransferase; LIAS, lipoic acid synthetase; Fer-1, ferrostatin-1; Nec-1, necrostatin-1; NAC, N-acetylcysteine.