Abstract
Stomach cancer is the fourth most common cancer worldwide. Identification of novel molecular therapeutic targets and development of novel treatments are critical. Against a panel of gastric carcinoma cell lines, the activity of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) was investigated. Adopting RT-PCR, Western blot and immunohistochemical techniques, we sought to determine molecular pharmacodynamic (PD) markers of sensitivity and investigate arylhydrocarbon (AhR) receptor-mediated signal transduction activation by 5F 203. Potent (IC50 ≤ 0.09 μmol/L), selective (>250-fold) in vitro antitumour activity was observed in MKN-45 and AGS carcinoma cells. Exposure of MKN-45 cells to 5F 203 triggered cytosolic AhR translocation to nuclei, inducing CYP1A1 (>50-fold) and CYP2W1 (~20-fold) transcription and protein (CYP1A1 and CYP2W1) expression. G2/M arrest and γH2AX expression preceded apoptosis, evidenced by PARP cleavage. In vivo, significant (P < .01) 5F 203 efficacy was observed against MKN-45 and AGS xenografts. In mice-bearing 5F 203-sensitive MKN-45 and 5F 203-insensitive BGC-823 tumours in opposite flanks, CYP1A1, CYP2W1 and γH2AX protein in MKN-45 tumours only following treatment of mice with 5F 203 (5 mg/kg) revealed PD biomarkers of sensitivity. 5F 203 evokes potent, selective antitumour activity in vitro and in vivo in human gastric cancer models. It triggers AhR signal transduction, CYP-catalysed bioactivation to electrophilic species causing lethal DNA double-strand breaks exclusively in sensitive cells. 5F 203 represents a novel therapeutic agent with a mechanism of action distinct from current clinical drugs, exploiting novel molecular targets pertinent to gastric tumourigenesis: AhR, CYP1A1 and CYP2W1. PD markers of 5F 203 sensitivity that could guide patient selection have been identified.