{Reference Type}: Journal Article
{Title}: Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (σ2) receptor and P-gp protein in the cytotoxic action: In vitro and in vivo activity in pancreatic tumors.
{Author}: Pati ML;Niso M;Spitzer D;Berardi F;Contino M;Riganti C;Hawkins WG;Abate C;
{Journal}: Eur J Med Chem
{Volume}: 144
{Issue}: 0
{Year}: Jan 2018 20
{Factor}: 7.088
{DOI}: 10.1016/j.ejmech.2017.12.024
{Abstract}: The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (σ2) 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 σ2 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, σ2-targeting appeared to allow alternative tumor cell death mechanisms, leading to potent and less toxic off-targets toxicities compared to other thiosemicarbazones devoid of σ2-targeting.