Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (σ 2) receptor and P-gp protein in the cytotoxic action: In vitro and in vivo activity in pancreatic tumors

Eur J Med Chem. 2018 Jan 20;144:359-371. doi: 10.1016/j.ejmech.2017.12.024. Epub 2017 Dec 8.

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.

Keywords: Mithocondrial superoxide; Multifunctional compounds; Pancreatic cancer; Sigma-2 receptors; Thiosemicarbazones.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Receptors, sigma / antagonists & inhibitors*
  • Receptors, sigma / metabolism
  • Structure-Activity Relationship
  • Thiosemicarbazones / chemical synthesis
  • Thiosemicarbazones / chemistry
  • Thiosemicarbazones / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Chelating Agents
  • Receptors, sigma
  • Thiosemicarbazones
  • sigma-2 receptor