Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

Abstract

Purpose: Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.Experimental Design: AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.Results: We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) signifi-cantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and in vivo using mouse models of AML. In addition, these redoxtargeted combination therapies are effective in eradicating ALL cells in vitro and in vivo.Conclusions: Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Of note, since the cytotoxicity of conventional anti-cancer therapies largely relies on efficient ROS accumulation, the augmented antioxidant capacity of cancer cells constitutes a key determinant of therapy-resistance [286][287][288]. At the same time, given the strong dependency of malignant cells to their antioxidant systems, interfering with their redox control can induce OS-dependent cell death [289]. Since the NRF2 signaling plays a key role in tumorigenesis, malignant progression [290][291][292] and drug sensitivity [293][294][295], this transcription factor has emerged as a promising therapeutic target [16,282,[296][297][298].…”

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…This important role of glutaminase in glutamine metabolism makes it a valuable target for cancer therapy. The application of glutaminase inhibitors attenuates the glutamine to glutamate conversion, elevates intracellular ROS level and impairs antioxidant GSH production in cancer cells (15,115,116). Furthermore, the combination of glutaminase inhibitors with chemotherapy agents also increased sensitivity of cancer cells to chemotherapy in pancreatic cancer and ovarian cancer (59, 117, 118).…”

Metabolic Plasticity of Acute Myeloid Leukemia

“…Glutamine is an important metabolite for the synthesis of the tripeptide glutathione, the prime ROS scavenger (Figure 4). The utilization of glutamine has shown to be essential for redox control in AML [103]. Gregory et al (2018) showed that CB-839 inhibited glutathione production, that this provoked accumulation of mitochondrial ROS in multiple AML types, and subsequently apoptotic cell death (Figure 5).…”