Abstract
Tumor cells-even if nonauxotrophic-are often highly sensitive to arginine deficiency. We hypothesized that arginine deprivation therapy (ADT) if combined with irradiation could be a new treatment strategy for glioblastoma (GBM) patients because systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle in vitro study was performed with ADT being mimicked by application of recombinant human arginase or arginine-free diets. ADT inhibited two-dimensional (2-D) growth and cell-cycle progression, and reduced growth recovery after completion of treatment in four different GBM cell line models. Cells were less susceptible to ADT alone in the presence of citrulline and in a three-dimensional (3-D) environment. Migration and 3-D invasion were not unfavorably affected. However, ADT caused a significant radiosensitization that was more pronounced in a GBM cell model with p53 loss of function as compared with its p53-wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase or argininosuccinate lyase protein expression and not abrogated by the presence of citrulline. The radiosensitizing potential was maintained or even more distinguishable in a 3-D environment as verified in p53-knockdown and p53-wildtype U87-MG cells via a 60-day spheroid control probability assay. Although the underlying mechanism is still ambiguous, the observation of ADT-induced radiosensitization is of great clinical interest, in particular for patients with GBM showing high radioresistance and/or p53 loss of function. Mol Cancer Ther; 17(2); 393-406. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."
Highlights
Arginine is a semi-essential amino acid required for numerous cellular processes such as protein synthesis and arginylation, polyamine production, metabolism of other amino acids and nucleotides, as well as creatine, urea, and nitric oxide (NO) synthesis [1, 2]
arginine deprivation therapy (ADT) by rh-Arginase inhibits 2-D GBM cell growth and recovery Arginine deprivation over a period of 48 hours by exposure to a modified rhA was recently found to be cytotoxic for GBM
GBM cells differ in their 2-D growth response to ADT and in their enzyme equipment for intracellular arginine synthesis; Citrulline partially compensates the arginase-induced loss of regrowth capacity but not the growth arrest
Summary
Arginine is a semi-essential amino acid required for numerous cellular processes such as protein synthesis and arginylation, polyamine production, metabolism of other amino acids and nucleotides, as well as creatine, urea, and nitric oxide (NO) synthesis [1, 2]. The intracellular arginine pool is usually fueled by arginine uptake from the blood and interstitial fluid through cationic amino acid transporters (CAT), via protein degradation, Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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