Altered Glutamine Metabolism and Therapeutic Opportunities for Lung Cancer

Abstract

Disordered cancer metabolism was described almost a century ago as an abnormal adaptation of cancer cells to glucose utilization especially under hypoxic conditions; the so-called Warburg effect. Greater research interest in this area in the last several decades has led to the recognition of the critical coupling of specific malignant phenotypes such as increased proliferation and resistance to programmed cell death (apoptosis) with altered metabolic handling of key molecules that are essential for normal cellular metabolism. The altered glucose metabolism frequently encountered in cancer cells has been exploited for cancer diagnosis and treatment. More recently, the role of other glycolytic pathway intermediates as well as alternative pathways for energy generation and macromolecular synthesis in cancer cells has become recognized. Especially, the important role of altered glutamine metabolism in the malignant behavior of cancer cells and the potential exploitation of this cellular adaptation for therapeutic targeting has emerged as an important area of cancer research in the last decade. Expectedly, attempts to exploit this understanding for diagnostic and therapeutic ends are running apace with the elucidation of the complex metabolic alterations that accompany neoplastic transformation. Because lung cancer is a leading cause of cancer death with limited curative therapy options, careful elucidation of the mechanism and consequences of disordered cancer metabolism in lung cancer is warranted. This review provides a concise, systematic overview of the current understanding of the role of altered glutamine metabolism in cancer and how these findings intersect with current and future approaches to lung cancer management.

The tolerance and safety of 4-Demethyl-4-cholesteryloxypenclomedine [DM-CHOC-PEN] in Adolescent and Young Adult (AYA) subjects with advanced malignancies

“…This is in contrast to DM-PEN (Figure 1) and other analogs that require hepatic activation [7]. These observations have led to a proposed mechanism whereby DM-CHOC-PEN associates with erythrocyte surface membranes, penetrates the BBB and brain parenchyma and is transported into intracerebral tumors with L-glutamine, with which it shares common structural moieties [11][12][13]. Thus, DM-CHOC-PEN may be killing micro-metastases, inhibiting DNA repair (an alkylating agent), and inducing an 'abscopal' immune effect [11].…”

“…The current Phase I AYA protocol (DTI-024) has been approved by the FDA, CTEP, IRBs and permits enrollments of subjects at escalating doses of 50, 75, and 100 mg/m 2 once every 21 days [13]. New subjects can be added to a higher dose level after one or more subjects receives 2-cycles of the drug at a given dose level (to avoid accumulative toxicity).…”

Glutamine and its use in selected oncology settings

“…1,2 GLN contributes 30-35% of the amino acid-based nitrogen in plasma, 3,4 plays an important role in gluconeogenesis, 4 and serves as a fuel for rapidly dividing and growing cells (e.g. enterocytes and lymphocytes).…”

“…3 GLN transports ammonia in a non-toxic form, from the peripheral tissue to visceral organs, where it is excreted in the urine. 4 GLN is also used by the gut and kidneys for acid-base homeostatis. 4 Healthy subjects have an endogenous GLN production of 50-80 g/day.…”

“…4 GLN is also used by the gut and kidneys for acid-base homeostatis. 4 Healthy subjects have an endogenous GLN production of 50-80 g/day. 6 GLN forms 25% of the free amino acid pool in the extracellular fluid and 60% in the skeletal muscle, 7 which is the main site for L-glutamine synthesis and storage.…”