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

Vaidehi Agrawal, Jung Hee Woo, Jeremy P. Mauldin, Chanhee Jo, Everett M. Stone, George Georgiou, Arthur E. Frankel

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)51-64
Number of pages14
JournalAnti-Cancer Drugs
Volume23
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Argininosuccinate Synthase
Arginase
Citrulline
Cobalt
Neoplasms
Umbilicus
Cell Line
Poisons
Mesothelioma
Small Cell Lung Carcinoma
Osteosarcoma
Acute Myeloid Leukemia
Patient Selection
Culture Media
Arginine
human arginase I
Prostate
Pancreas
Hepatocellular Carcinoma
Melanoma

Keywords

  • acute myeloid leukemia
  • arginase
  • arginine depletion argininosuccinate synthetase
  • cancer

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research
  • Oncology

Cite this

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. / Agrawal, Vaidehi; Woo, Jung Hee; Mauldin, Jeremy P.; Jo, Chanhee; Stone, Everett M.; Georgiou, George; Frankel, Arthur E.

In: Anti-Cancer Drugs, Vol. 23, No. 1, 01.2012, p. 51-64.

Research output: Contribution to journalArticle

Agrawal, Vaidehi ; Woo, Jung Hee ; Mauldin, Jeremy P. ; Jo, Chanhee ; Stone, Everett M. ; Georgiou, George ; Frankel, Arthur E. / 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. In: Anti-Cancer Drugs. 2012 ; Vol. 23, No. 1. pp. 51-64.
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