Glutamine Supplementation as an Anticancer Strategy: A Potential Therapeutic Alternative to the Convention

Abstract

Glutamine, a multifaceted nonessential/conditionally essential amino acid integral to cellular metabolism and immune function, holds pivotal importance in the landscape of cancer therapy. This review delves into the intricate dynamics surrounding both glutamine antagonism strategies and glutamine supplementation within the context of cancer treatment, emphasizing the critical role of glutamine metabolism in cancer progression and therapy. Glutamine antagonism, aiming to disrupt tumor growth by targeting critical metabolic pathways, is challenged by the adaptive nature of cancer cells and the complex metabolic microenvironment, potentially compromising its therapeutic efficacy. In contrast, glutamine supplementation supports immune function, improves gut integrity, alleviates treatment-related toxicities, and improves patient well-being. Moreover, recent studies highlighted its contributions to epigenetic regulation within cancer cells and its potential to bolster anti-cancer immune functions. However, glutamine implementation necessitates careful consideration of potential interactions with ongoing treatment regimens and the delicate equilibrium between supporting normal cellular function and promoting tumorigenesis. By critically assessing the implications of both glutamine antagonism strategies and glutamine supplementation, this review aims to offer comprehensive insights into potential therapeutic strategies targeting glutamine metabolism for effective cancer management.

Keywords: amino acids; cachexia; cancer; cancer therapy; glutamine; metabolism; nutrition.

Figure 1

Regulation and roles of glutamine metabolism in cancer. Cancer cells take up glutamine (Gln) through glutamine transporters, including SLC1A5 (ASCT2), SLC38A1, and SLC6A14. For glutaminolysis, glutamine is transported into the mitochondrial matrix through the SLC1A5 variant and subsequently catalyzed to glutamate (Glu) by glutaminases (GLS1 and GLS2). Glutamine and glutamate are indirectly responsible for the uptake of other amino acids, such as leucine (Leu) and cystine (Cys), via the SLC7A5 (LAT1) and SLC7A11 (xCT) transporters, respectively. Glutamate is converted to α-KG through GLUD1 or aminotransferases (GPT2, GOT1 and GOT2). α-KG contributes to epigenetic modifications by histones and DNA demethylation. The resulting intermediates can supply bioenergetics through the TCA cycle and support the biosynthesis of proteins, nucleotides, and lipids. In addition, glutamine metabolism maintains redox balance via GSH synthesis and reduces oxidative stress via NADPH synthesis. Glutamine metabolism in cancer is regulated by oncogenes (KRAS, MYC, and PI3KCA, etc.) and tumor suppressor genes (p53 and RB, etc.) (red lightning).

Figure 2

Glutamine concentrations in cancer. Upper left: Regional glutamine deficiency. Tumors inherently have low glutamine levels compared to benign adjacent tissues. Furthermore, tumor core regions display low glutamine levels compared to the periphery, and this regional glutamine deficiency in tumors promotes de-differentiation through the inhibition of histone demethylation. Upper right: the competition for glutamine between tumor cells and immune cells in the tumor microenvironment (TME) causes glutamine deficiency, affecting immune cells’ function. Lower left: systemic glutamine deficiency. Blood glutamine concentration changes according to the balance between significant organ producers (liver, skeletal muscle, lung, adipocytes, etc.) and consumers (brain, kidney, gut, liver, immune cells, etc.) in health and catabolic situations. In health, there is a balance between glutamine synthesis and degradation. In contrast, under stress and/or catabolic conditions such as cancer, organs responsible for glutamine synthesis (such as the skeletal muscle tissue) reduce its production, and at the same time, immune cells increase their demand for glutamine. Cancer patients have significantly decreased serum glutamine levels compared to healthy individuals; under this condition, the endogenous synthesis of glutamine does not appear to meet the human body’s demand, and glutamine assumes the role of a conditionally essential amino acid.

Figure 3

Benefits and drawbacks of targeting glutaminolysis in cancer.

Figure 4

Benefits and drawbacks of glutamine supplementation in cancer.