Modulation of arginine metabolic pathways as the potential anti-tumor mechanism of recombinant arginine deiminase.
Arginine deiminase (ADI), currently in clinical trials, has various biological activities including anti-proliferation, anti-angiogenesis and inhibition of inducible nitric oxide synthase (iNOS). To recognize limitations and therapeutic applications, the mechanism of ADI modulation of arginine metabolic pathways was investigated. MCF-7 and A549 cells have notable different sensitivity to recombinant ADI (rADI) and express diverse argininosuccinate synthase (AS) activity, which regenerates arginine. Due to compartmentalization of arginine, utilization of arginine for protein synthesis occurs from either the intracellular arginine pool or the citrulline-arginine-regeneration pathway, whereas for polyamine synthesis, utilization is only from the intracellular arginine pool. Modulating AS activity or introducing rADI intracellularly to reduce intracellular arginine regeneration may expand therapeutic applications of rADI.
Shen
Li-Jiuan
LJ
Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, 404B, Los Angeles, CA 90089-9121, USA.
Beloussow
Karin
K
Shen
Wei-Chiang
WC
D000230:Adenocarcinoma / Q000473:pathology; D001120:Arginine / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011073:Polyamines; D014176:Protein Biosynthesis / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D011073:Polyamines; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D006867:Hydrolases; C019723:arginine deiminase