br Depletion of serum amino acids Currently the only antican

Depletion of serum amino acids Currently, the only anticancer agents that directly target amino Cyclosporine mg metabolism are bacterial l-asparaginases (from Escherichia coli and Erwinia chrysanthemi), which are FDA-approved for treatment of pediatric and adult ALL. A potential complication of using bacterial enzymes is the production of neutralizing antibodies during treatment. PEGylation decreases immunogenicity and prolongs half-life, and PEGylated E. colil-asparaginase is also FDA-approved for ALL therapy. Numerous clinical trials are currently evaluating the efficacy of l-asparaginases in treating a range of hematological malignancies [9]. Mammalian cells can generate asparagine from aspartate and glutamine via the enzyme asparagine synthetase (ASNS). However, some cancer cells, including leukemic lymphoblasts, lack expression of ASNS, and therefore rely on blood serum asparagine supply (i.e., they are asparagine auxotrophic). l-Asparaginases catalyze the deamidation of asparagine, resulting in a rapid depletion of this amino acid in serum [9]. Importantly, l-asparaginases also catalyze deamidation of glutamine. Because glutamine has diverse functions in cancer cell metabolism and is required for ASNS-mediated asparagine synthesis, serum glutamine depletion probably contributes to the therapeutic effects of l-asparaginases [9]. Similar approaches are being investigated for treatment of arginine auxotrophic tumors. The urea cycle enzyme argininosuccinate synthetase (ASS)1 catalyzes formation of argininosuccinate from citrulline and aspartate (Fig. 1). Argininosuccinate in turn is converted by argininosuccinate lyase (ASL) to arginine. Although most cells can synthesize arginine de novo using this pathway, loss of ASS1 expression occurs in certain cancers, rendering them arginine auxotrophic [10]. ASS1-deficiency supports proliferation by increasing aspartate supply for pyrimidine synthesis (Fig. 1) [11]. PEGylated bacterial arginine deiminase (ADI-PEG20) and recombinant human arginase 1 (rhArg1-PEG, or BCT-100) deplete serum arginine, and both are currently the subject of clinical trials (up to Phase III) [10]. As with l-asparaginase, a complication associated with bacterial-derived ADI-PEG20 is its immunogenicity. Although rhArg1-PEG lacks antigenicity, its KM for arginine is approximately tenfold higher than that of ADI-PEG20 [10]. A further potential limitation of this strategy is that cancer cells can rapidly develop resistance to arginine deprivation through re-expression of ASS1 [10].
Nitrogen transfer reactions: glutamine and its metabolic neighbors After glucose, the most rapidly consumed nutrient by many cultured cancer cell lines is glutamine [4,5], the most abundant amino acid in blood serum [7]. Although other amino acids, which are consumed at much lower rates than glutamine, collectively account for the majority of carbon mass in proliferating mammalian cells, glucose- and glutamine-derived carbon each still constitute 5–10% of total dry cell mass [5]. Glutamine is a major carbon source for nonessential amino acid synthesis (Fig. 2), and therefore glutamine-derived carbon is over-represented in cellular protein [5]. Furthermore, the amide and α-nitrogen atoms of glutamine respectively account for 11% and 17% of cellular nitrogen in cultured lung cancer cells [5]. In rapidly proliferating cells including immune cells, enterocytes of the small intestine and some cancer cells, glutamine plays a major part in cellular energetics and redox homeostasis, in addition to supplying biosynthetic reactions with nitrogen and/or carbon (Fig. 2) [7]. Indeed, although mammalian cells can synthesize glutamine de novo, elevated demand can render them dependent on an exogenous supply during rapid proliferation [7]. A number of oncogenic signaling pathways and transcription factors drive the reprogramming of cellular glutamine metabolism during tumorigenesis [7,12,13]. Although we focus below on glutamine catabolism as a potential therapeutic target, glutamine synthesis also has crucial roles in some cancer cells (Box 1).