TY - JOUR
T1 - New imidazo[2,1-b][1,3,4]thiadiazole aerivatives anhibit FAK phosphorylation and potentiate the antiproliferative effects of gemcitabine through modulation of the human equilibrative nucleoside transporter-1 in peritoneal mesothelioma
AU - Petri, Giovanna L. I.
AU - Pecoraro, Camilla
AU - Randazzo, Ornella
AU - Zoppi, Silvia
AU - Cascioferro, Stella Maria
AU - Parrino, Barbara
AU - Carbone, Daniela
AU - Hassouni, Btissame E. L.
AU - Cavazzoni, Andrea
AU - Zaffaroni, Nadia
AU - Cirrincione, Girolamo
AU - Diana, Patrizia
AU - Peters, Godefridus J.
AU - Giovannetti, Elisa
N1 - Funding Information: This work was partially supported by grants to Elisa Giovannetti from “The Law Offices of Peter G. Angelos Grant” of the Mesothelioma Applied Research Foundation (E.G), CCA grant 2018, AIRC Start-Up grant, Dutch Cancer Society grants (KWF project#11957), and Polish National Science Center project 2018/31/B/NZ7/02909 (G.J.P, E.G). Publisher Copyright: © 2020 International Institute of Anticancer Research. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Background/Aim: A new class of imidazo[2,1b][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.
AB - Background/Aim: A new class of imidazo[2,1b][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.
KW - 1-b][1
KW - 3
KW - 4]thiadiazole compounds
KW - FAK
KW - Gemcitabine
KW - Human equilibrative nucleoside transporter-1
KW - Imidazo[2
KW - Mesothelioma
UR - http://www.scopus.com/inward/record.url?scp=85090260689&partnerID=8YFLogxK
U2 - https://doi.org/10.21873/anticanres.14494
DO - https://doi.org/10.21873/anticanres.14494
M3 - Article
C2 - 32878779
SN - 0250-7005
VL - 40
SP - 4913
EP - 4919
JO - Anticancer research
JF - Anticancer research
IS - 9
ER -