Biology subjects

Youn, B.-S.

Publications and source records attributed to Youn, B.-S..

5 recordsLinked to original sources

bioRxiv2025

Sequential Activation of Senescence and Apoptosis by ONG41008 Eliminated the Human Pancreatic Ductile Adenocarcinoma in nude mice and xenografted human lung cancer

Current therapeutic limitations associated with pancreatic ductal adenocarcinoma (PDAC) are still evident. We have found that ONG41008, the first human synthetic polyphenol, is able to eradicate PDAC in a nude mouse model. ONG41008 is known to potently attenuate human TGF-{beta} production, inducing both anti-fibrotic capacity and anticancer potential through senescence-coupled apoptosis (SCA). These interesting observations closely paralleled ONG41008s ability to inhibit PDACs, and as expected, ONG41008 alone was able to actually ablate engrafted PDACs in nude mice. Interestingly, the anti-PD 1 developed by MSD did not appear to act on immune activation of exhausted Cd8+ T cells in the tumor microenvironment (TME), but primarily on engrafted PDAC blood vessels. These observations support the latest report from MSD. A549 cells known to be a well appreciated human lung adenocarcinoma cell line were treated with ONG41008. Consistent with the prior observations ONG41008 notably induced SCA. and when A549 cells were xenografted into mice daunting tumor formations were noticed. Upon stimulation with ONG41008 via direct intramural injection of these tumors tumor volumes were rapidly regressed. Taken together, we believe that ONG41008 could be a multifaceted anti-cancer agent not only against PDAC but also against other aggressive cancers such as lung cancer.

cancer biology↗

bioRxiv2023

Apoptosis-coupled senescence causes cancer cell senotherapy

Although new generations of anti-cancer modalities have been accumulated involving immuno-oncology cancers remain prevailing. This implies the current understanding of cancer cell biology is far from satisfactory. Curation of cancers is extremely rare. We hypothesized what could be the easiest Achilles Hill of cancer cells such that simple administration can jab cancer cells to be knocked out. Of conspicuous differences between cancer cells and normal cells, for example, metabolism, hypoxia, anaerobic glycolysis, uncontrolled cell proliferation, etc. exist. What could be the easiest and the most reliable anti-cancer modalities? We discovered one was cancer cell senescence (CCS) because cancer cells are the most presenescent (old) cells. We utilized a synthetic polyphenol designated as ONG41008. ONG41008 was able to induce massive senescence of pathologic myofibroblasts (pMFBs) and a vast majority of representative human cancer cells as well as a line of primary NSCLCs. All these cells turned out to be senescence-associated beta-galactosidase (SAbGAL) positive to different degrees, which does not mean real senescence is occurring in these cells. ONG41008 did not harm normal cells and elicited massive senescence in pMFBs without apoptosis. However, ONG41008 caused massive senescence as well as apoptosis in cancer cells. In other words, ONG41008 was capable of sensing intracellular molecular environments between normal cells, cancer cells, and pMFBs. This molecular recognition capability prompted us to explore how ONG4008 behaved on A549 (a human lung adenocarcinoma), PANC1(malignant human ductal adenocarcinoma), and mdr+PC3 (multidrug-resistant human prostate cancer). TP53, p21, and p16 were induced and/or nuclear relocated, suggesting that ONG41008 was recognized by these cells. ONG41008 drove A549 and PANC1 at G2/M phase arrest during 48 hrs, resulting in massive mitotic collapse. All cells died. Moreover, the cisplatin-resistant mdr+PC3 was also eliminated by ONG41008. An array of common components of apoptosis were activated, and especially, induction of Mcl1 was especially notable. These senolytics features were reported to oncogene-induced-senescence (OIS), in which the expression of over two activated oncogenes in the embryonic fibroblasts caused massive senescence and cell death as well. And the signature expression of Mcl1, an anti-apoptotic protein (a long form), was notable but two kinds of short forms are pro-apoptotic proteins. OIS was conducted in vitro cell culture models and whether or not the presence of OIS counterpart in vivo remains to be delineated. Taken together, we discovered a synthetic polyphenol referred to as ONG41008 was both senogenic and senolytic and its senescent impacts may make the cell cycles of the ONG41008-treated cancer cells immensely arrested at the G2/M phase, leading to mitotic slippage and cell death. This interesting observation may be able to create an idealistic anti-cancer modality, specifically killing cancer cells, but normal cells remain unharmed.

cancer biology↗

bioRxiv2021

Liberation from fibrogenesis or tumorigenesis via cellular senescence by a noble small molecule

BackgroundUncontrolled proliferative diseases such as fibrosis or cancer can be fatal. We previously found that a compound containing a chromone scaffold, ONG41008, had potent anti-fibrotic effects in diseased human lung myofibroblasts but not normal human lung fibroblasts. MethodsWe investigated the effects of ONG41008 on tumor cells, and compared these effects with those in pathogenic myofibrotic cells and normal fibroblasts cells. FindingsStimulation of A549 lung carcinoma epithelial cells with ONG41008 resulted in cellular senescence, indicating that dysregulated cell proliferation is common to fibrotic cells and tumor cells. Replicative senescence of A549 cells resulted in multinucleation, which was followed by oncogene-induced senescence. There was significant upregulation of expression and nuclear translocation of p-TP53 and p16 in ONG41008-treated A549 cells, and all cells died after 72 hr. Similar effects occurred after ONG41008 treatment in several human aggressive cancer cell lines such as PANC1, MCF7, PC3, or primary non-small cell lung carcinoma cells. Unlike cisplatin, ONG41008 was not toxic to normal human lung fibroblasts or primary prostate epithelial cells, suggesting 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 or increased lactate dehydrogenase levels in aged or diseased cells. InterpretationTo our best knowledge, this is the first study to show that a small molecule can arrest uncontrolled proliferation during fibrogenesis or tumorigenesis in vitro. ONG41008 could be a potential drug for a broad range of fibrotic or tumorigenic diseases. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSThe notion that aging is a disease and that diseases occur as a consequence of aging was first put forward by David Sinclair and colleagues (Aging Cell;14(4):497-510). There are biological systems that provide evidence for this notion; for example, somatic cells can revert to embryonic cells, producing younger somatic cells. This phenomenon underlies induced pluripotent stem cells. Another example is that some types of jellyfish can live forever. These examples suggest that a counter-aging program exists in animals. Human diseases are the manifestations of cell aging generated by the accumulation of somatic mutations. Aged and pathogenic cells are senescent, so a drug that specifically targeted senescent cells might initiate a cellular program that could ameliorate age-associated disease. Indeed, the kinase inhibitor dasatinib induces cellular senescence (Clin Ther 2007 29:2289-2308). In 2017, two drugs that target senescent cells were identified: quercetin and fisetin. These drugs selectively kill senescent cells, and are referred to as senolytic drugs or senotherapeutics (Aging 2017 8;9(3):955-963). Although it is established that senescent cells accumulate in cancer and idiopathic pulmonary fibrosis (Nat Commun 2017 23;8 :14532), the effect of senolytic drugs in these diseases is largely unknown. Added value of this studyThis study characterized a novel drug, termed ONG41008, which was found to have both senogenic and senolytic effects in cell-based assays. ONG41008 induced senescence in myofibroblasts and several cancer cell lines representative of aggressive human cancers, which was followed by cell death. Importantly, ONG41008 exhibited essentially no toxicity on normal human lung fibroblasts or primary prostate epithelial cells. Implication of all the evidenceBased on our results, we believe that ONG41008 is a potent inducer of cellular senescence (replicative senescence and oncogene-induced senescence) and causes arrest of uncontrolled, pathogenic proliferation of myofibroblasts or cancer cells.

cell biology↗

bioRxiv2019

Discovery of a small molecule having both potent anti-fibrotic and anti-inflammatory capabilities

AbstractsIdiopathy pulmonary fibrosis (IPF) is an intractable and fatal human disorder. Our previous study showed that eupatilin exerted a potent anti-fibrotic effect on both in vitro fibrogenesis and bleomycin-induced lung fibrosis model (BLM). Subsequently, an analog called ONG41008 had been identified as a more potent anti-fibrotic than eupatilin and also showed a potent anti-inflammatory capability. Orally administered ONG41008 significantly improved onset of BLM in both prophylactic and therapeutic model and its therapeutic efficacy was similarly compared to or better than pirfenidone by measuring production of collagen and hydroxyproline. Staining collagen or SMA corroborated these results. As in vitro fibrogenesis models, DHLF (Diseased Human Lung Fibroblasts from IPF patients) and HSC (hepatic stellate cells) were used for direct effects of ONG41008 on pivotal cellular and molecular functions associated with pathogenic myofibroblasts; ONG41008 dismantled latent TGFb complex (LTC), generating inactive forms of TGF{beta}, likely limiting TGF{beta} to TGF{beta} receptor via depolymerization of F-actin and this blunted SMAD2/SMAD3 phosphorylation, thereby reprogramming EMT. A set of cell imaging studies and transcriptomic analysis were conducted to explore how ONG41008 elicited both anti-fibrotic and anti-inflammatory capabilities. Elastin (ELN) seemed to be a pioneering pharmacodynamic marker. It was also found that NOX4 played an important role in anti- fibrosis because it was functionally connected to major central nod proteins such as lysyl- oxidase (LOX) and numerous collagen family members in an ONG41008-specific fibrogenic interactome. Human NOX4 was significantly induced by TGF{beta} and completely knocked down by ONG41008. It has been shown that production of reactive oxygen species (ROS) led to activation of inflammasome. ONG41008 may be likely related to anti-inflammation, leading to a key protective effect on fibrogenesis. Concomitant with downregulation of NOX4, expression of macrophages homing chemokines, CCL2 and CCL7 were significantly attenuated by ONG41008. In vitro anti-inflammatory activities of ONG41008 were investigated in RAW264.7 cells, a mouse monocytic cell line stimulated with LPS. ONG41008 substantially attenuated TNF, CXCL10, CCL2 and CCL7, which are proinflammatory cytokine and important chemokines influencing T cells or macrophages. TNF was situated at the central nod in LPS-treated macrophages via an ONG41008-specific interactome analysis. Taken together, ONG41008 is a TGF{beta} biogenesis inhibitor, being a potent drug for a broad range of fibrotic diseases and could antagonize inflammatory diseases as well.

pharmacology and toxicology↗

bioRxiv2017

Small molecule-mediated reprogramming of epithelial-mesenchymal transition thereby blocking fibrosis

Fibrotic diseases are major causes of morbidity and mortality, and the epithelial-mesenchymal transition (EMT) plays a central role in the development of tissue/organ fibrosis. We discovered that eupatilin, a member of the chromone scaffold (CS)-containing compounds found ubiquitously in the plant kingdom, completely reversed fibrogenesis in vitro and substantially ameliorated bleomycin-induced lung fibrosis (BILF). Furthermore, eupatilin-induced growth arrest and morphological changes in primary fibroblasts derived from a patient with idiopathic pulmonary fibrosis (IPF). To better understand fibrosis, we established a mouse hepatic stellate cell (HSC) line that was robustly differentiated into myofibroblasts upon treatment with TGF{beta}. HSC-derived fibrogenesis was completely blocked by eupatilin, which caused dramatic morphological changes while inhibiting expression of EMT-related genes. The chemical groups linked to the 2nd carbon (C2), C3, C6, and C7 on the CS of eupatilin were essential for its anti-fibrogenic effects. Unlike eupatilin, pirfenidone failed to block HSC fibrogenesis and did not affect the morphology of HSCs or lung fibroblasts. Although pirfenidone affected local production of TGF{beta}, as reflected by a reduction in the TGF{beta} level in lung lysates of BILF model mice, eupatilin is likely to act via a different therapeutic mechanism. In particular, eupatilin had greater anti-fibrotic capacity and EMT-inhibitory activity and significantly attenuated the phosphorylation of Erk by TGF{beta}. Based on the interactome, Integrin{beta}3 seems to be a major player in integration of TGF{beta} signaling into the eupatilin-mediated anti-fibrosis. Our findings suggest that combinatorial use of eupatilin and pirfenidone may augment the therapeutic efficacy of IPF treatment.

cell biology↗