Uncontrolled proliferative diseases such as fibrosis or cancers are fatal human disorders. Previously, we found that a chromone-scaffold derivative called ONG41008 had a strong anti-fibrotic effect on in vitro fibrogenesis as well as in a murine lung fibrosis model. It later occurred to our attention that while ONG41008 remarkably attenuated proliferation of diseased human lung myofibroblasts (DHLF), resulting in replicative senescence (RS) typified by cell flatness, normal human lung fibroblasts were not affected. Video demonstration revealed that RS was evident within 48hr after ONG41008 treatment. No ONG41008 affected activated caspase 3 and mitochondrial membrane potential in DHLF. An interactome study suggested that metabolic shift, chromatin remodeling, or cell cycle control may be required for the RS. This observation prompted us to be engaged in the cellular senescence of tumor cells. Clearly, senescent cells were conspicuously but temporarily observed in A549, adenocarcinomic human alveolar epithelial cells, giving us confidence that dysregulated cell proliferation could be a common underlying principle conserved in both DHLF and A549. An early phase of stimulation of A549 by ONG41008 led to RS followed by multinucleation (MNC), which has been known to be oncogene-induced senescence (OIS). MNC was immediately followed by apoptosis. Concomitant with massive upregulation of p16 and translocation to the nuclei, complete cell death of the remaining A549 occurred. Induction and nuclear translocation of p21was also noted in both A549 and DHLF stimulated with ONG41008. No induction of TP53 was seen but phosphorylation of TP53 was substantially increased in A549. Both immunocytochemistry and western blots corroborated these common senescent imaging features. With comparative analyses, it is clear that ONG41008 exhibited much lesser toxicity on normal human lung fibroblast than SAHA (suberoylanilide hydroxamic acid) and Nintedanib. Taken together, all these studies strongly suggest that ONG41008 is a potent inducer of RS or OIS, presumably resulting in cessation of the cell cycle are at G1 or G2 stage and/or systemic cell death. To our best knowledge, the liberation of uncontrolled proliferative cells from fibrogenesis or tumorigenesis by a small molecule in vitro is an unprecedented case. ONG41008 could be a potential and safe drug for a broad range of fibrotic diseases or tumorigenic diseases.
P2-177: TARGETING DELTA133P53 ISOFORM WITH SMALL MOLECULE COMPOUNDS TOWARDS THE TREATMENT OF CELLULAR SENESCENCE-ASSOCIATED DISEASES