A select thiosemicarbazone copper(II) complex induces apoptosis in gastric cancer and targets cancer stem cells reducing pluripotency markers

• Published in: European journal of medicinal chemistry 2024-12, Vol.280, p.116994, Article 116994
• Main Authors: Fabra, David, Melones-Herrero, Jorge, Velazquez-Gutierrez, Javier, Matesanz, Ana I., Aliseda, Patricia D., Figueiras, Sofia, Aguilar-Rico, Francisco, Calés, Carmela, Sánchez-Pérez, Isabel, Quiroga, Adoracion G.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cancer stem cells; Cell Line, Tumor; Cell Proliferation - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper; Copper - chemistry; Copper - pharmacology; DNA interaction; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Gastric cancer; Humans; Metallodrug; Molecular Structure; Neoplastic Stem Cells - drug effects; Oxidative stress; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Structure-Activity Relationship; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116994

Copper(II)-based complexes are promising candidates as anti-cancer agents due to their ability to target cancer cells. Here we describe the synthesis and characterization of two copper(II) thiosemicarbazone complexes with the ligands 4-(dimethylamino)benzaldehyde N4-methylthiosemicarbazone (HL1) and 4-(dimethylamino)benzaldehyde N4-(4-(dimethylamino)phenylthiosemicarbazone (HL2) and general formula [Cu(L)2]. The complexes show stability in aqueous solution with 1 % of DMSO that allows to stablish its solution profile in biological buffers. Compound [Cu(L1)₂] lipophilicity was lower than [Cu(L2)₂], however, its solubility in biological buffer was not only better but also its DLS and ζ-potential data. In vitro studies demonstrate a higher cytotoxic effect of [Cu(L1)₂] on gastric cancer cells. The proposed mechanism of action consists in the generation of free radicals that induce DNA lesions, oxidative stress and ultimately autophagy deregulation and apoptosis. Additionally, [Cu(L1)₂] is equally active on gastric cancer stem cells and tumor cells resistant to cisplatin. More importantly, stem cells treated with [Cu(L1)₂] show a downregulation of pluripotency markers such as TWIST, NANOG and OCT4. Overall, our results with [Cu(L1)₂] prompt a significant advancement in the development of rational-designed pharmaceuticals for combating cancer. [Display omitted] •Two new Cu complexes designed to improve thiosemicarbazones biological performance.•Solution studies allowed to select one candidate which showed cytotoxicity activity on tumor cells resistant to cisplatin.•The select Cu complex can eliminate cancer stem cells responsible for cancer recurrence and treatment resistance.•The compound demonstrates downregulation of pluripotency markers in Cancer Stem Cells.