Kidney cancer rapidly acquires resistance to antiangiogenic agents, such as sunitinib, developing an aggressive migratory phenotype (facilitated by c-Metsignal transduction). The Aryl hydrocarbon receptor (AhR) has recently been postulated as a molecular target for cancer treatment. Currently, there are two antitumor agent AhR ligands, with activity against renal cancer, that have been tested clinically: aminoflavone (AFP 464, NSC710464) and the benzothiazole (5F 203) prodrug Phortress. Our studies investigated the action of AFP 464, the aminoflavone pro-drug currently used in clinical trials, and 5F 203 on renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis and cell migration. Both compounds caused cell cycle arrest and apoptosis but only 5F 203 potently inhibited the migration of TK-10, Caki-1 and SN12C cells as well as the migration signal transduction cascade, involving c-Met signaling, in TK-10 cells. Current investigations are focused on the development of nano-delivery vehicles, apoferritin-encapsulated benzothiazoles 5F 203 and GW610, for the treatment of renal cancer. These compounds have shown improved antitumor effects against TK-10 cells in vitro at lower concentrations compared with a naked agent.
International journal of molecular sciences. 2020 May 18*** epublish ***
Boris Itkin, Alastair Breen, Lyudmila Turyanska, Eduardo Omar Sandes, Tracey D Bradshaw, Andrea Irene Loaiza-Perez
Department of Oncology, Hospital General de Agudos Juan Fernandez, C1425 CABA Buenos Aires, Argentina., School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham NG72RD, Nottinghamshire, UK., Faculty of Engineering, University of Nottingham, University Park, Nottingham NG72RD, Nottinghamshire, UK., Facultad de Medicina, Instituto de Oncología Ángel H. Roffo (IOAHR), Universidad de Buenos Aires, Área Investigación, Av. San Martin 5481, C1417 DTB Buenos Aires, Argentina.