2 ) receptor and P-gp protein in the cytotoxic action: In?vitro and in?vivo activity in pancreatic tumors

摘要

Abstract The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (σ 2 ) receptor was recently proposed as a promising target for pancreatic cancer therapy, we explored our previously developed multifunctional thiosemicarbazones, designed to synergistically impair cell energy levels, by targeting σ 2 and P-gp proteins and chelating Iron. A deconstruction approach was herein applied by removing one function at a time from the potent multifunctional thiosemicarbazones 1 and 2 , to investigate the contribution to cytotoxicity of each target involved. The results from in?vitro (panel of pancreatic tumor cells) and in?vivo experiments (C57BL/6 bearing KP02 tumor), suggest that while the multifunctional activity was not required for the antitumor activity of these thiosemicarbazones, σ 2 -targeting appeared to allow alternative tumor cell death mechanisms, leading to potent and less toxic off-targets toxicities compared to other thiosemicarbazones devoid of σ 2 -targeting. Graphical abstract Display Omitted Highlights ? Metal Chelation, σ 2 and P-gp proteins interaction in multifunctional thiosemicarbazones. ? Deconstruction of potent multifunctional thiosemicarbazones. ? Multifunctional ligands reduce pancreatic cancer growth in mouse stroma dense model. ? Diverse death pathways from compounds sharing N , N -dimethyl-thiosemicarbazone. ? Different sensitization of cells useful for developing tailored treatments.