Cytotoxicity of human recombinant arginase I (Co)-PEG5000 in the presence of supplemental L-citrulline is dependent on decreased argininosuccinate synthetase expression in human cells

• DOI: 10.1097/cad.0b013e32834ae42b
• Publication Date: 2011-10-04T22:32:56Z
• Authors: Vaidehi Agrawal; Jung Hee Woo; Jeremy P. Mauldin; Chanhee Jo; Everett M. Stone; George Georgiou; Arthur E. Frankel
• Keywords: Argininosuccinate synthase; Argininosuccinate lyase

Human recombinant arginase I cobalt [HuArgI (Co)] coupled with polyethylene glycol 5000 (Co)-PEG5000] has shown potent in-vitro depletion of arginine from tissue culture medium. We now show that HuArgI (Co)-PEG5000 is toxic to almost all cancer cell lines and some normal primary cells examined. In contrast, in combination supplemental L-citrulline selectively cytotoxic a fraction human culture, including melanomas, mesotheliomas, acute myeloid leukemias, hepatocellular carcinomas, pancreas adenocarcinomas, prostate lung osteosarcomas, small carcinomas. Unfortunately, subset tissues also sensitive supplementation, umbilical endothelial cells, bronchial epithelium, neurons, renal epithelial cells. further sensitivity predicted by the level cellular argininosuccinate synthetase protein expression measured immunoblots. By comparing 3-day 7-day exposure L-citrulline, tumor on short-term assay are resistant consistent induction expression. On basis these results, we hypothesize supplementation may be an attractive therapeutic agent for synthetase-deficient tumors. These findings stimulate development this molecule aid identification toxicities better selection patients who will potentially respond therapy.