New Imidazo[2,1- b][1,3,4]Thiadiazole Derivatives Inhibit FAK Phosphorylation and Potentiate the Antiproliferative Effects of Gemcitabine Through Modulation of the Human Equilibrative Nucleoside Transporter-1 in Peritoneal Mesothelioma

Anticancer Res. 2020 Sep;40(9):4913-4919. doi: 10.21873/anticanres.14494.

Abstract

Background/aim: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease.

Materials and methods: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells.

Results: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 μM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1).

Conclusion: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.

Keywords: FAK; Mesothelioma; gemcitabine; human equilibrative nucleoside transporter-1; imidazo[2,1-b][1,3,4]thiadiazole compounds.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Synergism
  • Equilibrative Nucleoside Transporter 1 / genetics*
  • Focal Adhesion Kinase 1 / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Mesothelioma / drug therapy
  • Mesothelioma / pathology
  • Molecular Structure
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / pathology
  • Phosphorylation / drug effects
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Equilibrative Nucleoside Transporter 1
  • Imidazoles
  • SLC29A1 protein, human
  • Thiadiazoles
  • imidazo(2,1-b)(1,3,4)thiadiazole
  • Deoxycytidine
  • gemcitabine
  • Focal Adhesion Kinase 1
  • PTK2 protein, human