A Small Molecule That Promotes Cellular Senescence Prevents Fibrogenesis and Tumorigenesis

Uncontrolled proliferative diseases, such as fibrosis or cancer, can be fatal. We previously found that a compound containing the chromone scaffold (CS), {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008, had potent antifibrogenic effects associated with EMT or cell-cycle control resembling tumorigenesis. We investigated the effects of {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 on tumor cells and compared these effects with those in pathogenic myofibroblasts. Stimulation of A549 (lung carcinoma epithelial cells) or PANC1 (pancreatic ductal carcinoma cells) with {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 resulted in robust cellular senescence, indicating that dysregulated cell proliferation is common to fibrotic cells and tumor cells. The senescence was followed by multinucleation, a manifestation of mitotic slippage. There was significant upregulation of expression and rapid nuclear translocation of p-TP53 and p16 in the treated cancer cells, which thereafter died after 72 h confirmed by 6 day live imaging. {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 exhibited a comparable senogenic potential to that of dasatinib. Interestingly, {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 was only able to activate caspase-3, 7 in comparison with quercetin and fisetin, also containing CS in PANC1. {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 did not seem to be essentially toxic to normal human lung fibroblasts or primary prostate epithelial cells, suggesting {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 can distinguish the intracellular microenvironment between normal cells and aged or diseased cells. This effect might occur as a result of the increased NAD/NADH ratio, because {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 restored this important metabolic ratio in cancer cells. Taken together, this is the first study to demonstrate that a small molecule can arrest uncontrolled proliferation during fibrogenesis or tumorigenesis via both senogenic and senolytic potential. {"type":"entrez-protein","attrs":{"text":"ONG41008","term_id":"1139545353"}}ONG41008 could be a potential drug for a broad range of fibrotic or tumorigenic diseases.