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

Giovanna Li Petri, Girolamo Cirrincione, Stella Maria Cascioferro, Barbara Parrino, Daniela Carbone, Patrizia Diana, Ornella Randazzo, Camilla Pecoraro, Godefridus J. Peters, Ornella Randazzo, Giovanna Li Petri, Daniela Carbone, Btissame E.L. Hassouni, Silvia Zoppi, Giovanna L.I. Petri, Andrea Cavazzoni, Elisa Giovannetti, Nadia Zaffaroni

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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.
Original languageEnglish
Pages (from-to)4913-4919
Number of pages7
JournalAnticancer Research
Volume40
Publication statusPublished - 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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