Abstract
Despite the common usage of radiotherapy for the treatment of human non-small-cell lung cancer (NSCLC), cancer therapeutic efficacy and outcome with ionizing radiation remains a challenge. Here, we report the antitumor effects and mechanism of a novel benzothiazole derivative PB01 (4-methoxy-cyclohexane carboxylic acid [2-(3,5-dimethyl-isoxazole-4-yl) sulpanil-benzothiazole-6-yl]-amide) in radiation-resistant human NSCLC cells. PB01 treatment is cytotoxic because it induces reactive oxygen species, ER stress, Bax, cytochrome c expression, the ATR-p53-GADD45ɑ axis, and cleavage of caspase-3 and -9. Additionally, we found that radio-resistant A549 and H460 subclones, named A549R and H460R, respectively, show enhanced epithelial-to-mesenchymal transition (EMT), whereas PB01 treatment inhibits EMT and mediates cell death through ER stress and the ATR axis under radiation exposure in radio-resistant A549R and H460R cells. Together, these results suggest that PB01 treatment can overcome radio-resistance during radiotherapy of NSCLC.
Highlights
Despite the common usage of radiotherapy for the treatment of human non-small-cell lung cancer (NSCLC), cancer therapeutic efficacy and outcome with ionizing radiation remains a challenge
These results indicate that PB01 inhibits the proliferation of NSCLC cells
Accumulating evidence indicates that radiation is one of the causes of epithelial-to-mesenchymal transition (EMT); it is necessary to understand the relationship between radiation and EMT, the characteristic of novel targets that can fight cancer progression, and damaged normal tissue induced by radiotherapy[47]
Summary
Despite the common usage of radiotherapy for the treatment of human non-small-cell lung cancer (NSCLC), cancer therapeutic efficacy and outcome with ionizing radiation remains a challenge. We found that radio-resistant A549 and H460 subclones, named A549R and H460R, respectively, show enhanced epithelial-to-mesenchymal transition (EMT), whereas PB01 treatment inhibits EMT and mediates cell death through ER stress and the ATR axis under radiation exposure in radio-resistant A549R and H460R cells. Though IR causes cytotoxicity in cancer cells, increasing studies have suggested that IR mediates the malignancy and radio-resistance in various cancer cell types including lung, hepatocellular carcinomas, and g liomas[6,7,8]. Overcoming drug resistance or radio-resistance factors, including EMT phenotype via radiation, hypoxia and nutrient deprivation, suggests potential cancer therapy strategies, and developing new compound and combination strategy to overcome chemo- or radio-resistance may lead to more effective therapeutic strategy. By targeting IR-activated EMT pathways, PB01 may be effective at countering IR in these cell types and improving their radio-therapeutic response
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