Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia

by Selleckchem | Aug 17 2023

Introduction: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.

Methods: To investigate the in vitro effects of CB-839 on CLL cells, we tested CB-839 alone and in combination with ibrutinib, venetoclax, or AZD-5991 on the HG-3 and MEC-1 CLL cell lines and on primary CLL lymphocytes.

Results: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed.

Discussion: Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.

Comments:

The given text describes a study investigating the effects of CB-839, a glutaminase-1 (GLS-1) inhibitor, on chronic lymphocytic leukemia (CLL) cells. The study aimed to determine the potential of CB-839 as a treatment for CLL and its interactions with other commonly used CLL drugs, namely ibrutinib, venetoclax, and AZD-5991.

The researchers conducted in vitro experiments using the HG-3 and MEC-1 CLL cell lines, as well as primary CLL lymphocytes. They observed that CB-839 treatment resulted in dose-dependent reductions in GLS-1 activity and glutathione synthesis. Furthermore, the treated cells exhibited increased metabolism of mitochondrial superoxide and impaired energy metabolism, leading to decreased oxygen consumption rate, depletion of the adenosine triphosphate (ATP) pool, and inhibition of cell proliferation.

When CB-839 was combined with venetoclax or AZD-5991 in the cell lines, it demonstrated synergistic effects, resulting in increased apoptosis (cell death) rates and inhibition of cell proliferation. However, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed in the primary lymphocytes.

The discussion of the study highlights that CB-839 has limited efficacy as a standalone treatment for CLL. Although CB-839 combined with venetoclax or AZD-5991 showed synergism in the cell lines, it did not exhibit significant effects in primary CLL lymphocytes. Additionally, CB-839 did not show synergy with ibrutinib, one of the widely used CLL drugs.

Overall, these findings suggest that while CB-839 may have some potential as a CLL treatment, its effectiveness appears to be limited, especially when used in combination with existing CLL drugs. Further research is needed to explore alternative treatment strategies and overcome resistance mechanisms in CLL cells.