A select thiosemicarbazone copper(II) complex induces apoptosis in gastric cancer and targets cancer stem cells reducing pluripotency markers
David Fabra, Jorge M. Herrero, Javier Velázquez-Gutiérrez, Ana I. Matesanz, Patricia Delgado Aliseda, Sofía Figueiras, Francisco Aguilar-Rico, Carmela Calés, Isabel Sánchez‐Pérez, Adoración G. Quiroga
Abstract
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 (HL 1 ) and 4-(dimethylamino)benzaldehyde N4-(4-(dimethylamino)phenylthiosemicarbazone (HL 2 ) 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(L 1 )₂] lipophilicity was lower than [Cu(L 2 )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(L 1 )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(L 1 )₂] is equally active on gastric cancer stem cells and tumor cells resistant to cisplatin. More importantly, stem cells treated with [Cu(L 1 )₂] show a downregulation of pluripotency markers such as TWIST , NANOG and OCT4 . Overall, our results with [Cu(L 1 )₂] prompt a significant advancement in the development of rational-designed pharmaceuticals for combating cancer. • 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.