Abstract
The present study targets the Proline-Glutamine-Asparagine-Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy. The study also reviewed the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure. The non-essential amino acids such as proline (Pro), glutamine (Gln), asparagine (Asn) and arginine (Arg) support this promise. While these amino acids can be synthesized endogenously in normal cells, however many human tumors, ranging from leukemia to solid cancers, do not produce sufficient amounts of these amino acids to support their growth. Our bodies are capable of producing the conditionally non-essential amino acids proline, glutamine, asparagine, and arginine. Nonetheless, they are necessary for the development of highly proliferative cells, including malignancies. These amino acids are expressed in lower quantities in many malignancies, necessitating their importation from the environment. While the biosynthesis of these amino acids is inter-connected but can be intervened individually through inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials and targeting proline starvation is in pre-clinical development. The most important obstacle of these therapies is drug resistance, mostly due to the reactivation of the key enzymes involved in the biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways, via transcriptional, epigenetic, and posttranscriptional mechanisms. This study provided a broader scope of targeting amino acid starvation beyond the current individual one. Perhaps it is time to think globally when designing strategies to target amino acid starvation therapy. This may eventually lead to the development of effective strategies in cancer treatment.