The antitumour activity of 2‐(4‐amino‐3‐methylphenyl)‐5‐fluorobenzothiazole in human gastric cancer models is mediated by AhR signalling
| Autor: | Yu-Ling Wang, Ying Luo, Yang Yan, Jihong Zhang, Tracey D. Bradshaw, Malcolm F. G. Stevens, Dong-Fang Shi, Cheng Xi, Tao Tang, Ying Liu |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
molecular pharmacodynamic (PD) markers Intracellular Space Mice Nude Antineoplastic Agents Apoptosis 03 medical and health sciences 0302 clinical medicine Cytochrome P-450 Enzyme System Western blot Stomach Neoplasms In vivo Cell Line Tumor medicine Animals Humans arylhydrocarbon (AhR) receptor Cell Proliferation Mice Inbred BALB C stomach cancer medicine.diagnostic_test Chemistry Original Articles Cell Cycle Checkpoints Cell Biology In vitro Gene Expression Regulation Neoplastic Thiazoles 030104 developmental biology Receptors Aryl Hydrocarbon Mechanism of action Cell culture 030220 oncology & carcinogenesis Cancer research Molecular Medicine Original Article CYP2W1 medicine.symptom Signal transduction CYP‐catalysed bioactivation DNA Damage Signal Transduction |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| DOI: | 10.1111/jcmm.14869 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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