2. Academic Validation
  3. BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics

BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics

  • Mol Metab. 2025 Apr:94:102113. doi: 10.1016/j.molmet.2025.102113.
Se Seul Im 1,  Jihyeon Seo 1,  Ji Eun You 1,  Hye Won Bang 1,  YongHwan Kim 2,  Jiyeon Kweon 2,  Yongsub Kim 2,  Dong-Myung Shin 2,  Jaekyoung Son 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Brain Korea 21 project, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
  • 2 Department of Cell and Genetic Engineering, Brain Korea 21 project, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
  • 3 Department of Biochemistry and Molecular Biology, Brain Korea 21 project, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. Electronic address: jaekson@amc.seoul.kr.
PMID: 39961401 DOI: 10.1016/j.molmet.2025.102113
Abstract

Objectives: Increased expression of Glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of Cancer, including breast, lung, and pancreatic Cancer. G9a Histone Methyltransferase inhibitors may have Anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a Histone Methyltransferase Inhibitor, can inhibit Glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.

Methods: The effects of BIX on Mitochondrial Metabolism in PDAC cells were evaluated by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.

Results: BIX significantly inhibited the growth of PDAC cells, both in vitro and in vivo, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP+/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-l-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced Apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a Histone Methyltransferase. One Jumonji-domain Histone Demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.

Conclusions: Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.

Keywords

BIX01294; Glutaminase; Glutathione; KDM6B; Pancreatic cancer.

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