Inhibition of copper chaperones sensitizes human and canine osteosarcoma cells to carboplatin chemotherapy

Abstract

Osteosarcoma (OSA) is the most common primary bone cancer in children, adolescents and dogs. Current combination surgical and chemotherapeutic treatments have increased survival. However, in recurrent or metastatic disease settings, the prognosis significantly decreases, representing an urgent need for better second-line and novel chemotherapeutics. The current gold standard for combination chemotherapy in OSA often includes a platinum agent, for example, cisplatin or carboplatin. These platinum agents are shuttled within the cell via copper transporters. Recent interest in targeting copper transport has been directed towards antioxidant protein 1 (Atox1) and copper chaperone for superoxide dismutase 1 (CCS), with Atox1 demonstrating the ability to aggregate platinum agents, preventing them from forming DNA adducts. DC_AC50 is a small molecule inhibitor of both Atox1 and CCS. To assess the impact of targeting these pathways on chemotherapy response, two human and two canine OSA cell lines were utilized. After treatment with single agent or combination drugs, cell viability was evaluated and pharmacological synergism calculated using the combination index method. Apoptosis, cell cycle distribution, clonogenic survival and migration were also evaluated. DC_AC50 synergised with carboplatin in combination treatment of human and canine OSA cells to reduce cancer cell viability. DC_AC50-treated cells were significantly less mitotically active, as demonstrated by decreased expression of phospho-histone H3 and cell cycle analysis. DC_AC50 also potentiated carboplatin-induced apoptosis in OSA cells and decreased clonogenic survival. Finally, DC_AC50 reduced the migratory ability of OSA cells. These results justify further investigation into inhibiting intracellular copper chaperones as a means of reducing/preventing acquired chemotherapy resistance.

FGF13 enhances resistance to platinum drugs by regulating hCTR1 and ATP7A via a microtubule‐stabilizing effect

“…57,58 DC_AC 50, a small molecule inhibitor of Atox1, has been found to limit copper intake and sensitize cancer cells to platinum drugs. 59,60 In this study, we found that FGF13 simultaneously regulates the expression and distribution of hCTR1 and ATP7A to reduce drug influx and promote drug sequestration and efflux when cancer cells are exposed to platinum drugs. The FGF13-induced regulation of hCTR1 and ATP7A depends on the microtubule-stabilizing effect of FGF13.…”

“… 57 , 58 DC_AC 50, a small molecule inhibitor of Atox1, has been found to limit copper intake and sensitize cancer cells to platinum drugs. 59 , 60 …”

Identification of a Novel Cuproptosis-Related Gene Signature for Prognostic Implication in Head and Neck Squamous Carcinomas

“…To provide deeper insight into the role played by the prognostic risk score model in HNSC, we performed some further analyses. Several lines of evidence suggest that copper and its transporter could affect the outcome of chemotherapy [ 51 , 52 , 53 ]. So, we predicted the sensitivity towards chemotherapeutics in both high- and low-risk groups.…”

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy

“…It has been shown that Atox1 may participate in the regulation of genes encoding superoxide dismutase 3 [37], pluripotency factor OCT4 [38], and NADPH oxidase organizer p47phox [39]. Deletion of Atox1 results in increased resistance to cDDP [40,41], perhaps due, at least in part, to impairment of nuclear targeting of Pt drugs to elicit DNA damages of the lethal effects [42]. and then to ATP7A/ATP7B at the Trans-Golgi Network (TGN) in the cytosol via the help of glutathione (GSH).…”