New gold (III) cyanide complex TGS 121 induces ER stress, proteasome inhibition and death of Ras-hyperactivated cells

• Published in: Toxicology in vitro Vol. 88; p. 105556
• Main Authors: Lipiec, Szymon, Gurba, Agata, Agnieszczak, Izabela M., Szczepankiewicz, Andrzej Antoni, Szymański, Przemysław, Taciak, Przemysław, Szczepaniak, Remigiusz, Szeleszczuk, Łukasz, Nieznanska, Hanna, Włodarczyk, Jakub, Fichna, Jakub, Bialy, Lukasz P., Mlynarczuk-Bialy, Izabela
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2023
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - toxicity; Cell Line, Tumor; Cyanides - toxicity; ER-stress; Gold (III) cyanide complex; Gold - chemistry; Gold - toxicity; NIH-3T3; Platinum - chemistry; Proteasome; Proteasome Endopeptidase Complex; Ras; TGS 121; NIH-3T3; Gold (III) cyanide complex; TGS 121; ER-stress; Ras; Proteasome
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2023.105556

Metal-based agents in cancer therapy, like cisplatin and its derivates, have established clinical applications but also can induce serious side effects. Thus, metallotherapeutic alternatives for platinum derivatives are developed and intensively studied. Platinum is replaced by several transition metals including gold. Especially gold (III) complexes can have the same square-planar structure and are isoelectric with platinum (II). Hence, they are developed as potential anti-cancer drugs. Thus, our group projected and developed a group of novel cyanide-based gold (III) complexes.
Within this work, we aimed to characterize the safety and effectivity of one of them, TGS 121. TGS 121 in our preliminary work was selective for Ras-hyperactivated cells. Here we studied the effects of the novel complex in cancerous Ras-3 T3 and non-cancerous NIH-3 T3 cells. The complex TGS 121 turned out to be non-toxic for NIH-3 T3 cells and to induce death and alternations in Ras-hyperactivated cells. We found induction of ER stress, mitochondria swelling, proteasome inhibition, and cell cycle block. Moreover, TGS 121 inhibited cell migration and induced the accumulation of perinuclear organelles that was secondary to proteasome inhibition.
Results presented in this report suggest that stable gold-cyanide TGS 121 complex is non-toxic, with a targeted mechanism of action and it is promising in anticancer drug discovery.
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•Novel cyanide‑gold (III) TGS121 complex is less toxic for noncancer cells.•TGS121 induces death of cancerous Ras-hyperactivated cells.•TGS121 inhibits proteasome, induces ER-stress and mitochondria swelling.•TGS121 induces block in G2/M, inhibits cell migration and reduces cell adhesion surface.