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CB-839 induces reversible dormancy in lung tumor-cells.

Azemat Jamshidi-Parsian1, Samir V Jenkins2, Amy Tran3

  • 1Department of Environmental Health Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

European Journal of Pharmacology
|August 19, 2024
PubMed
Summary

The glutaminase inhibitor CB-839 selectively reduces lung tumor cell function and survival by temporarily inhibiting glutamine metabolism. This reversible effect suggests CB-839 may induce cancer cell dormancy.

Keywords:
CB-839GLS1 inhibitorGlutaminaseLung cancer

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Glutaminase inhibitors are investigated as cancer therapeutics.
  • Understanding CB-839's molecular mechanisms in lung cancer is crucial.

Purpose of the Study:

  • Elucidate CB-839's effects on lung tumor versus non-tumor cell lines.
  • Investigate the molecular mechanisms of CB-839 action.

Main Methods:

  • Cell viability assays (NADPH dehydrogenases, ATP, mitochondrial reductase).
  • Clonogenic survival assays.
  • Glutaminase activity and glutamine consumption assays.
  • Cell cycle, apoptosis, necrosis, and trypan blue exclusion assays.

Main Results:

  • CB-839 demonstrated tumor-specific inhibition of cellular functions and dose-dependent reduction in clonogenic survival (IC50: 10-90 nM).
  • CB-839 reduced glutaminase (GLS1) activity and glutamine consumption in tumor cells, with no effect on non-tumor cells.
  • Effects were reversible upon drug removal; efficacy was amplified under hypoxia.
  • Minimal impact on cell cycle, apoptosis, or necrosis observed.

Conclusions:

  • CB-839 exhibits tumor-specific efficacy through reversible glutamine metabolism inhibition.
  • The drug's action suggests induction of cancer cell dormancy, particularly under hypoxic conditions.