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Review
. 2022 Sep 12;41(1):271.
doi: 10.1186/s13046-022-02485-0.

Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy

Peijie Zheng  1 , Chuntao Zhou  1 , Liuyi Lu  1 , Bin Liu  1 , Yuemin Ding  2   3   4
Affiliations
Review

"VSports注册入口" Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy

Peijie Zheng et al. J Exp Clin Cancer Res. .

Abstract

Elesclomol is an anticancer drug that targets mitochondrial metabolism. In the past, elesclomol was recognized as an inducer of oxidative stress, but now it has also been found to suppress cancer by inducing cuproptosis. Elesclomol's anticancer activity is determined by the dependence of cancer on mitochondrial metabolism. The mitochondrial metabolism of cancer stem cells, cancer cells resistant to platinum drugs, proteasome inhibitors, molecularly targeted drugs, and cancer cells with inhibited glycolysis was significantly enhanced VSports手机版. Elesclomol exhibited tremendous toxicity to all three kinds of cells. Elesclomol's toxicity to cells is highly dependent on its transport of extracellular copper ions, a process involved in cuproptosis. The discovery of cuproptosis has perfected the specific cancer suppressor mechanism of elesclomol. For some time, elesclomol failed to yield favorable results in oncology clinical trials, but its safety in clinical application was confirmed. Research progress on the relationship between elesclomol, mitochondrial metabolism and cuproptosis provides a possibility to explore the reapplication of elesclomol in the clinic. New clinical trials should selectively target cancer types with high mitochondrial metabolism and attempt to combine elesclomol with platinum, proteasome inhibitors, molecularly targeted drugs, or glycolysis inhibitors. Herein, the particular anticancer mechanism of elesclomol and its relationship with mitochondrial metabolism and cuproptosis will be presented, which may shed light on the better application of elesclomol in clinical tumor treatment. .

Keywords: Anticancer drugs; Cancer; Cancer stem cells; Clinical trials; Cuproptosis; Drug safety; Elesclomol; Mitochondrial metabolism V体育安卓版. .

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Conflict of interest statement

The authors declare that the study was conducted in the absence of any business or financial relationship that could be interpreted as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Enhanced mitochondrial metabolism sensitizes cancer cells to elesclomol. Cancer cells highly dependent on mitochondrial metabolism are sensitive to elesclomol, including cancer stem cells, drug-resistant cancer cells, and glycolysis-inhibiting cancer cells. Both TICs in ovarian cancer and GSCs in glioblastoma are associated with cancer recurrence and are highly dependent on mitochondrial metabolism. Drug-resistant cancer cells, including bortezomib-resistant breast cancer cells, cisplatin-resistant melanocytes and lung cancer cells, and vemurafenib-resistant melanocytes, increase their dependence on mitochondrial metabolism in the development of drug resistance. PDK inhibitor DCA enhances mitochondrial metabolism in melanoma cells by shifting their metabolism from glycolysis to oxidative phosphorylation. In addition, hypoxia in solid tumors reduces the intensity of mitochondrial metabolism, and the degree of tumor hypoxia is positively correlated with the serum LDH levels of the patients. Patients with low serum LDH levels are sensitive to elesclomol. ATP: adenosine triphosphate; DCA: dichloroacetate; GSCs: glioblastoma stem cells; LDH: lactate dehydrogenase; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinases; TICs: tumor-initiating cells
Fig. 2
Fig. 2
Schematic diagram of the mechanism of elesclomol-induced cell death. Elesclomol shuttles inside and outside the cell to selectively transport extracellular Cu(II) to mitochondria, where Cu(II) accumulated in mitochondria induces ROS production and triggers cuproptosis. FDX1, a critical enzyme in the occurrence of pyroptosis, reduces Cu(II) to Cu(I) in mitochondria while promoting the lipoylation of DLAT, an enzyme participating in the formation of the PDH complex and affecting the mitochondrial TCA cycle. The reduced Cu(I) binds to lipoylated DLAT to promote its oligomerization, ultimately leading to the occurrence of cuproptosis. FDX1 also promotes Fe-S synthesis, while Cu(I) inhibits this process. Fe-S is an essential component of LIAS and ETC, the key enzymes in DLAT lipoylation, but its relationship with cuproptosis is unclear. In addition, the regulation of intracellular Cu(I) levels by membrane copper ionophores, such as SCL31A1 and ATP7B, is also associated with the occurrence of cuproptosis. DLAT: dihydrolipoamide S-acetyltransferase; ETC: electron transfer chain; FDX1: ferredoxin 1; Fe-S: iron-sulfur proteins; LA: lipoamide; LIAS: lipoyl synthase; PDH: pyruvate dehydrogenase; ROS: reactive oxygen species; TCA: tricarboxylic acid cycle
Fig. 3
Fig. 3
Cancers highly dependent on mitochondrial metabolism. Cancers such as melanoma, breast cancer, and ovarian cancer show spontaneous enhancement of mitochondrial metabolism. Cancer stem cells of glioblastoma, ovarian cancer, cholangiocarcinoma, and other cancers highly depend on mitochondrial metabolism. Increased dependence on mitochondrial metabolism is seen in drug-resistant cancer cells generated in some anticancer treatments, including cisplatin-resistant melanoma and hepatocellular carcinoma from conventional chemotherapies and 5-FU-resistant colon cancer, BRAF inhibitor-resistant melanoma from molecularly targeted drugs, and EGFR inhibitor-resistant non-small cell lung cancer. 5FU: 5-Fluorouracil; BRAF: v-Raf murine sarcoma viral oncogene homolog B1; EGFR: epidermal growth factor receptor
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