Decursinol Angelate Inhibits Glutamate Dehydrogenase 1 Activity and Induces Intrinsic Apoptosis in MDR-CRC Cells

Colorectal cancer (CRC) was the second most commonly diagnosed worldwide and common cause of cancer-related deaths in Europe 2020. After CRC patients’ recovery, many cases a patient’s tumor returns develops chemoresistance, which has remained major challenge worldwide. We previously published our novel findings on role DA inhibiting activity GDH1 using silico enzymatic assays. No studies have been conducted so far to explain inhibitory against glutamate dehydrogenase MDR-CRC cells. developed multidrug-resistant colorectal cell line, HCT-116MDR, after treatment with cisplatin 5-fluorouracil. confirmed MDR phenotype by evaluating expression MDR1, ABCB5, extracellular vesicles, polyploidy, DNA damage response markers comparison parental HCT-116WT (HCT-116 wild type). Following confirmation, we determined IC50 performed clonogenic assay for efficacy decursinol angelate (DA) HCT-116MDR multidrug resistant). Subsequently, evaluated interactions important regulating redox homeostasis death. markedly downregulated at 50 75 μM 36 h, directly correlated reduced Krebs cycle metabolites α-ketoglutarate fumarate. also observed systematic dose-dependent downregulation TERT, ERCC1 γH2AX. Similarly, antioxidant downregulated. The intrinsic apoptosis were notably upregulated manner. results further validated flow cytometry TUNEL assay. Additionally, knockdown both corresponded decreased γH2AX, catalase, SOD1 Gpx-1, an eventual increase markers. In conclusion, inhibition increased ROS production, proliferation