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

Abstract

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.

Targeting the glutamine metabolism to suppress cell proliferation in mesenchymal docetaxel-resistant prostate cancer

“…Moreover, inhibition of Gln uptake decreased tumour growth and metastasis [ 36 ]. Glutaminolysis inhibition has generally reduced disease recurrence risk and metastases in several tumour entities [ 35 , 37 ]. Therefore, the influence of Gln on the clonogenic potential, migration, invasion, and adhesion was investigated within this study.…”

Cancer stem cells: a target for overcoming therapeutic resistance and relapse

“…Targeting CSCs through the inhibition of glutaminolysis, which is the process of converting glutamine-to-glutamate via the enzyme, glutaminase (GLS), is a promising metabolic interference strategy 431 . GLS1 is associated with different types of cancer, and the GLS1 inhibitor, BPTES, combined with the phosphodiesterase-5 inhibitor, zaprinast, increases the sensitivity of pancreatic CSCs to radiotherapy and promotes apoptosis by increasing the level of intracellular ROS 431 . The first glutaminase inhibitor, DON, was isolated from Peruvian soil and induces apoptosis of breast CSCs 444 .…”

“…Targets of glycolysis include rate-limiting enzymes, transporters, and other complex regulators [428][429][430] . GLUT1, a glucose transporter, has an important role in the maintenance of pancreatic, ovarian, and GBM CSCs 431 . WZB117, a specific GLUT1 inhibitor, successfully inhibits the self-renewal and tumorinitiating capacity of the CSCs in vitro 432 .…”

Nutritional Metabolomics in Diet–Breast Cancer Relations: Current Research, Challenges, and Future Directions—A Review

“…Additionally, it has been suggested that breast cancer cells, in order to maintain the life activities of tumor cells, absorb a lot of glutamate from blood circulation [158]. Studies have shown that glutamate, via activating the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), as well as promoting breast cancer cell invasion and migration through the activation of the MAPK pathway, could accelerate tumorigenesis [159,160]. In breast cancer, under normoxic conditions, glutamate was also found to enhance the activity of HIF1α [161].…”