Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells

Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks. These building blocks are mostly utilized in the synthesis of macromolecules and antioxidants for redox homeostasis. A recent study revealed the cellular and molecular interconnections between glutamine and cancer stemness in the cell. Researchers have increasingly focused on glutamine catabolism in their attempt to discover an effective therapy for cancer stem cells. Targeting catalytic enzymes in glutaminolysis, such as glutaminase (GLS), is achievable with small molecule inhibitors, some of which are in early-phase clinical trials and have promising safety profiles. This review summarizes the current findings in glutaminolysis of CSCs and focuses on novel cancer therapies that target glutaminolysis in CSCs.