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

Maria Laura Pati, Mauro Niso, Dirk Spitzer, Francesco Berardi, Marialessandra Contino, Chiara Riganti, William G. Hawkins, Carmen Abate

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish
Pages (from-to)359-371
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume144
DOIs
StatePublished - Jan 20 2018

Keywords

  • Mithocondrial superoxide
  • Multifunctional compounds
  • Pancreatic cancer
  • Sigma-2 receptors
  • Thiosemicarbazones

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