Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization

Tumor cells - even if non-auxotrophic - 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 since systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle in vitro study was performed with ADT been mimicked by application of recombinant human arginase or arginine-free diets. <p>ADT inhibited 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 3-D environment. Migration and 3-D invasion were not unfavourably affected. However, ADT caused a significant radiosensitization which was more pronounced in a GBM cell model with p53 loss of function as compared to its p53- wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase (ASS) or argininosuccinate lyase (ASL) 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. While 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.

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