Anticancer Properties of Hexosamine Analogs Designed to Attenuate Metabolic Flux through the Hexosamine Biosynthetic Pathway.
Christopher T SaeuiSagar R ShahBeatriz I Fernandez-GilCissy ZhangChristian AgatemorKris Dammen-BrowerMohit P MathewMatthew BuettnerPrateek GowdaPratik KhareAndrea Otamendi-LopezShuang YangHui ZhangAnne LeAlfredo Quinoñes-HinojosaKevin J YaremaPublished in: ACS chemical biology (2023)
Altered cellular metabolism is a hallmark of cancer pathogenesis and progression; for example, a near-universal feature of cancer is increased metabolic flux through the hexosamine biosynthetic pathway (HBP). This pathway produces uridine diphosphate N -acetylglucosamine (UDP-GlcNAc), a potent oncometabolite that drives multiple facets of cancer progression. In this study, we synthesized and evaluated peracetylated hexosamine analogs designed to reduce flux through the HBP. By screening a panel of analogs in pancreatic cancer and glioblastoma multiform (GBM) cells, we identified Ac 4 Glc2Bz─a benzyl-modified GlcNAc mimetic─as an antiproliferative cancer drug candidate that down-regulated oncogenic metabolites and reduced GBM cell motility at concentrations non-toxic to non-neoplastic cells. More specifically, the growth inhibitory effects of Ac 4 Glc2Bz were linked to reduced levels of UDP-GlcNAc and concomitant decreases in protein O-GlcNAc modification in both pancreatic cancer and GBM cells. Targeted metabolomics analysis in GBM cells showed that Ac 4 Glc2Bz disturbed glucose metabolism, amino acid pools, and nucleotide precursor biosynthesis, consistent with reduced proliferation and other anti-oncogenic properties of this analog. Furthermore, Ac 4 Glc2Bz reduced the invasion, migration, and stemness of GBM cells. Importantly, normal metabolic functions mediated by UDP-GlcNAc were not disrupted in non-neoplastic cells, including maintenance of endogenous levels of O-GlcNAcylation with no global disruption of N-glycan production. Finally, a pilot in vivo study showed that a potential therapeutic window exists where animals tolerated 5- to 10-fold higher levels of Ac 4 Glc2Bz than projected for in vivo efficacy. Together, these results establish GlcNAc analogs targeting the HBP through salvage mechanisms as a new therapeutic approach to safely normalize an important facet of aberrant glucose metabolism associated with cancer.
Keyphrases
- induced apoptosis
- cell cycle arrest
- papillary thyroid
- squamous cell carcinoma
- cell death
- stem cells
- endoplasmic reticulum stress
- clinical trial
- randomized controlled trial
- transcription factor
- molecular docking
- cell proliferation
- climate change
- emergency department
- mass spectrometry
- epithelial mesenchymal transition
- machine learning
- young adults
- escherichia coli
- oxidative stress
- mesenchymal stem cells
- study protocol
- cell migration
- candida albicans
- protein protein