Arginine deprivation and tumour cell death: Arginase and its inhibition

Wheatley, Denys N.; Philip, Ruth; Campbell, Elaine

doi:10.1007/978-1-4615-0247-0_26

Cited by 11 publications

(16 citation statements)

References 20 publications

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“…Means of five animals per dose. arginine-free medium but also from arginase-induced deficiency (34). This has led to the major limitation of ADI: it only kills cancer cells that are ASS deficient (9)(10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

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Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine Depletion

et al. 2007

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Section: Discussionmentioning

confidence: 99%

“…Arginase is a good enzyme to use to degrade arginine in culture because its product is ornithine, which cannot be recycled to arginine because the urea cycle is incomplete in most cultured cells (34), but the mechanism for this phenomenon has been an unresolved area. In our present studies, both native and pegylated rhArg (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine Depletion

et al. 2007

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“…Thus the decrease in cell number after 1 and 2 days of incubation in arginine-free medium indicates that arginine is an essential amino acid in IPEC-J2 cells. Previous reports showed that arginine is necessary for tumor cell growth (4,35,45); yet the cellular mechanisms that explain the requirement have not been established.…”

Section: Discussionmentioning

confidence: 99%

Arginine-induced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide

Bauchart-Thevret

Cui

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Bauchart-Thevret C, Cui L, Wu G, Burrin DG. Arginineinduced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide. Am J Physiol Endocrinol Metab 299: E899 -E909, 2010. First published September 14, 2010; doi:10.1152/ajpendo.00068.2010.-Arginine is an indispensable amino acid in neonates and is required for growth. Neonatal intestinal epithelial cells (IEC) are capable of arginine transport, catabolism, and synthesis and express nitric oxide (NO) synthase to produce NO from arginine. Our aim was to determine whether arginine directly stimulates IEC growth and protein synthesis and whether this effect is mediated via mammalian target of rapamycin (mTOR) and is NOdependent. We studied neonatal porcine IEC (IPEC-J2) cultured in serum-and arginine-free medium with increasing arginine concentrations for 4 or 48 h. Our results show that arginine enhances IPEC-J2 cell survival and protein synthesis, with a maximal response at a physiological concentration (0.1-0.5 mM). Addition of arginine increased the activation of mTOR, p70 ribosomal protein S6 (p70 S6) kinase, and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in a time-and dose-dependent manner. The arginine-induced protein synthesis response was not inhibited by the NO inhibitors nitro-Larginine methyl ester (L-NAME) and aminoguanidine, despite inducible NO synthase expression in IPEC-J2 cells. Moreover, protein synthesis was not increased or decreased in some cases by addition of an NO donor (S-nitroso-N-acetylpenicillamine), arginine precursors (proline and citrulline) in the absence of arginine, or insulin; Snitroso-N-acetylpenicillamine suppressed phosphorylation of mTOR, p70 S6 kinase, and 4E-BP1. We found a markedly higher arginase activity in IPEC-J2 cells than in primary pig IEC. Furthermore, mTOR inhibition by rapamycin partially (42%) reduced the arginineinduced protein synthesis response and phosphorylation of mTOR and 4E-BP1. We conclude that arginine-dependent cell survival and protein synthesis signaling in IPEC-J2 cells are mediated by mTOR, but not by NO. cell growth; p70 ribosomal protein S6 kinase; eukaryotic initiation factor 4E-binding protein 1; rapamycin; S-nitroso-N-acetylpenicillamine

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“…Plasma citrulline remained normal, and therefore the tumour cells must have converted citrulline to arginine fast enough to sustain relatively normal tumour growth rate (Wu and Morris, 1998;Philip et al, 2003). This makes it difficult to understand how previous in vivo work with arginase and arginine deiminase could have achieved significant inhibition of tumour growth under similar conditions (Bach and Swaine, 1965;Miyazaki et al, 1990), and begs further analysis of the ability of tumour cells to use citrulline in lieu of arginine (Wheatley and Campbell, 2002). Sugimura et al (1992) found that four out of five human melanoma cell lines deprived of arginine with arginine deiminase (EC 3.5.3.6) could not be rescued with citrulline, but grew when argininosuccinate, the immediate downstream intermediate, was supplied.…”

mentioning

confidence: 99%

Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

Wheatley

Campbell

2003

Br J Cancer

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Arginine deprivation causes death of up to 80% of cancer cell lines in vitro, but in the body, citrulline would be available as a convertible source of this amino acid in vivo. Some tumour cell lines, notably the vast majority of melanomas and hepatocellular carcinomas, tend to be deficient in argininosuccinate synthetase (EC 6.5.4.3.), and therefore cannot recycle citrulline to arginine. Argininosuccinate synthetase is present at levels that convert enough citrulline to arginine to allow limited growth in about half of a modest range of malignant cell types analysed in this study. Attempts to rescue cells that are unable to utilise citrulline with the immediate downstream product, argininosuccinate, had very limited success in a few tumour cell lines. Particularly noteworthy is the demonstration that argininosuccinate was totally incapable of rescuing cells that utilise citrulline efficiently, consistent with tight channelling (coupling) of argininosuccinate synthetase and argininosuccinate lyase in the urea cycle. The findings suggest that an excellent opportunity exists for further exploitation of arginine deprivation in the selective killing of tumour cells. Arginine is a vital amino acid for many metabolic processes other than protein synthesis (e.g. creatine production, polyamine synthesis and nitric oxide (NO) generation). Its removal from culture medium by medium formulation or arginase treatment quickly leads to death in B80% of tumour cell lines (Scott et al, 2000). The addition of citrulline can often circumvent this deficiency, but few cells are capable of its biosynthesis in culture. Arginine deficiency in vivo has been induced by various means, but is less effectively achieved because body homeostasis is too robust, and citrulline generation is difficult to control. Having successfully reduced L1210 cells in culture to negligible viability in 3-5 days with arginase (EC 3.5.3.1), citrulline supplementation in the continued presence of the enzyme partially circumvented the arginine deficiency. The rate of conversion became a rate-limiting factor, most noticeably in such fast-growing leukaemia as L1210 (Philip et al, 2003). In a corresponding in vivo study, arginase treatment of DBA/2 mice injected intraperitoneally with 1210 cells increased neither their survival time nor decreased tumour burden, despite plasma arginine falling to B1-2 mM level. Plasma citrulline remained normal, and therefore the tumour cells must have converted citrulline to arginine fast enough to sustain relatively normal tumour growth rate (Wu and Morris, 1998;Philip et al, 2003). This makes it difficult to understand how previous in vivo work with arginase and arginine deiminase could have achieved significant inhibition of tumour growth under similar conditions (Bach and Swaine, 1965;Miyazaki et al, 1990), and begs further analysis of the ability of tumour cells to use citrulline in lieu of arginine (Wheatley and Campbell, 2002). Sugimura et al (1992) found that four out of five human melanoma cell lines deprived of arginine w...

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Arginine deprivation and tumour cell death: Arginase and its inhibition

Cited by 11 publications

References 20 publications

Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine Depletion

Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine Depletion

Arginine-induced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide

Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells

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