A Small Molecule That Promotes Cellular Senescence Prevents Fibrogenesis and Tumorigenesis

Moon Kee Meang, Saesbyeol Kim, Ik Hwan Kim, Han Soo Kim, Byung Soo Youn

Research output: Contribution to journalArticlepeer-review

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 antifibro-genic 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 myo-fibroblasts. 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 mul-tinucleation, 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.

Original languageEnglish
Article number6852
JournalInternational journal of molecular sciences
Volume23
Issue number12
DOIs
Publication statusPublished - 2022 Jun 1

Keywords

  • cancer cell senolytics (CCS)
  • cellular senescence
  • senolytics
  • small molecule

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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