Related Experiment Video
Updated: Sep 6, 2025
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
A Small Molecule That Promotes Cellular Senescence Prevents Fibrogenesis and Tumorigenesis
Moon Kee Meang1, Saesbyeol Kim1, Ik-Hwan Kim2
1Osteoneurogen. Inc., Seoul 08501, Korea.
Abstract:
Uncontrolled proliferative diseases, such as fibrosis or cancer, can be fatal. We previously found that a compound containing the chromone scaffold (CS), ONG41008, had potent antifibrogenic effects associated with EMT or cell-cycle control resembling tumorigenesis. We investigated the effects of 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 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. ONG41008 exhibited a comparable senogenic potential to that of dasatinib. Interestingly, ONG41008 was only able to activate caspase-3, 7 in comparison with quercetin and fisetin, also containing CS in PANC1. ONG41008 did not seem to be essentially 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, because 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. ONG41008 could be a potential drug for a broad range of fibrotic or tumorigenic diseases.
Insights
ONG41008, a chromone scaffold compound, induces cellular senescence and death in cancer cells, similar to dasatinib. It shows potential as a drug for fibrotic and tumorigenic diseases by targeting uncontrolled proliferation.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Uncontrolled cell proliferation in diseases like fibrosis and cancer is often fatal.
- The compound ONG41008, containing a chromone scaffold (CS), demonstrated antifibrogenic effects linked to epithelial-mesenchymal transition (EMT) and cell-cycle control.
- Tumorigenesis shares characteristics with fibrotic processes, suggesting common therapeutic targets.
Purpose of the Study:
- To investigate the effects of ONG41008 on tumor cells.
- To compare its effects on cancer cells with those on pathogenic myofibroblasts.
- To evaluate ONG41008's potential as a therapeutic agent for proliferative diseases.
Main Methods:
- Stimulation of A549 (lung carcinoma) and PANC1 (pancreatic cancer) cells with ONG41008.
- Assessment of cellular senescence, multinucleation, and mitotic slippage.
- Analysis of p-TP53 and p16 expression and nuclear translocation.
- Live imaging to confirm cell death.
- Comparison of ONG41008's senogenic potential with dasatinib, quercetin, and fisetin.
- Evaluation of toxicity in normal human lung fibroblasts and primary prostate epithelial cells.
- Measurement of NAD/NADH ratios in treated cancer cells.
Main Results:
- ONG41008 induced robust cellular senescence and subsequent multinucleation in A549 and PANC1 cells.
- Significant upregulation and nuclear translocation of p-TP53 and p16 were observed in treated cancer cells, leading to cell death within 72 hours.
- ONG41008 demonstrated senogenic potential comparable to dasatinib and activated caspase-3, 7, unlike quercetin and fisetin.
- ONG41008 showed selective toxicity towards cancer cells, sparing normal fibroblasts and epithelial cells.
- The compound restored the NAD/NADH metabolic ratio in cancer cells.
Conclusions:
- ONG41008 effectively arrests uncontrolled proliferation in cancer cells via senogenic and senolytic mechanisms.
- The compound exhibits selective toxicity, distinguishing between normal and diseased/aged cells.
- Restoration of the NAD/NADH ratio may contribute to ONG41008's therapeutic effects.
- ONG41008 represents a potential therapeutic candidate for a wide range of fibrotic and tumorigenic diseases.
More Related Videos
07:39SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
13:59A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence
Published on: August 12, 2018
Related Concept Videos
02:15Replicative Cell Senescence
01:23Negative Regulator Molecules
01:16TGF - β Signaling Pathway
02:23Abnormal Proliferation
01:27Molecular Factors Affecting Cell Division
Several proteins function as internal regulators to ensure each cell cycle stage is completed faithfully before proceeding to the next. Regulator molecules may act directly or influence the activity or production of other...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...