Integrity and stability of the citrulline–arginine pathway in normal and tumour cell lines

Wheatley, Denys N.; Kilfeather, Ruth; Stitt, Alison; Campbell, Elaine

doi:10.1016/j.canlet.2005.01.004

Cited by 27 publications

(25 citation statements)

References 27 publications

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“…HCC and malignant melanoma are often auxotrophic for arginine (19). The mechanism of this arginine auxotrophy has been amply described in a number of reports (3,15,19,(29)(30)(31). In essence, these tumors reportedly lack ASS with which to regenerate arginine, which is indispensable for growth.…”

Section: Discussionmentioning

confidence: 99%

“…In essence, these tumors reportedly lack ASS with which to regenerate arginine, which is indispensable for growth. This absolute dependence on exogenous arginine in these tumors makes them particularly vulnerable to arginine depletion (19,29,31). ADI in its pegylated form, ADI-SS PEG 20,000mw (12,32), has now been shown to have in vitro and in vivo activities in HCC and malignant melanoma as reported in the recent phase II studies (9,10), although it does have a number of shortcomings.…”

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%

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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“…It has been observed that many tumor cells have a higher nutritional demand for exogenous arginine in comparison with normal cells. Thus, arginine may be a growth-limiting factor for such malignant cells [14,15]. Because of the complexity of arginine-dependent metabolic networks, the general molecular mechanism that triggers cell death in sensitive tumors on arginine deprivation is still not well understood.…”

Section: Introductionmentioning

confidence: 98%

Canavanine augments proapoptotic effects of arginine deprivation in cultured human cancer cells

et al. 2011

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Arginine deprivation achieved by means of recombinant arginine-degrading enzymes is currently being developed as a novel anticancer enzymotherapy. In this study, we showed that arginine deprivation in vitro profoundly and selectively sensitized human cancer cells of different organ origin to low doses of canavanine, an arginine analogue of plant origin. In sensitive cancer cells arginine starvation led to the activation of caspase-9, caspase-3 and caspase-7, cleavage of reparation enzyme, polyADP ribosyl polymerase, and DNA fragmentation, which are the typical hallmarks of intrinsic apoptosis realized by the mitochondrial pathway. Co-administration of canavanine significantly accelerated and enhanced apoptotic manifestations induced by arginine deprivation. The augmentation of canavanine toxicity for cancer cells was observed when either a formulated arginine-free medium or complete medium supplemented with bovine arginase preparation was used. Cycloheximide efficiently rescued malignant cells from canavanine-induced cytotoxicity under arginine deprivation, suggesting that it results mainly from canavanine incorporation into newly synthesized proteins. Cancer cells sensitive or resistant to arginine deprivation alone were not capable of restoring their proliferation after 24 h of combined treatment, whereas pseudonormal cells retained such ability. Our data suggest that the incorporation of canavanine into anticancer treatment schemes based on artificially created arginine starvation could be a novel strategy in tumor enzymochemotherapy.

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“…Recent studies have shown that a number of normal and transformed cell lines are incapable of using L-citrulline as a source of L-arginine synthesis. While fibroblasts and many other cell types can use L-citrulline as a source of L-arginine, human umbilical vein endothelial cells and some microvascular endothelial cells and tumor cells appear to be completely dependent on arginine for cell growth (95). As the possible therapeutic uses of L-citrulline supplementation expand, more studies are needed to determine the capacity of each cell type to use L-citrulline for L-arginine synthesis.…”

Section: Conversion Of L-citrulline To L-argininementioning

confidence: 99%

Therapeutic Use of Citrulline in Cardiovascular Disease

Romero

Platt

Caldwell

2006

Cardiovascular Drug Reviews

190

178

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L-citrulline is the natural precursor of L-arginine, substrate for nitric oxide synthase (NOS) in the production of NO. Supplemental administration L-arginine has been shown to be effective in improving NO production and cardiovascular function in cardiovascular diseases associated with endothelial dysfunction, such as hypertension, heart failure, atherosclerosis, diabetic vascular disease and ischemia-reperfusion injury, but the beneficial actions do not endure with chronic therapy. Substantial intestinal and hepatic metabolism of L-arginine to ornithine and urea by arginase makes oral delivery very ineffective. Additionally, all of these disease states as well as supplemental L-arginine enhance arginase expression and activity, thus reducing the effectiveness of L-arginine therapy. In contrast, L-citrulline is not metabolized in the intestine or liver and does not induce tissue arginase, but rather inhibits its activity. L-citrulline entering the kidney, vascular endothelium and other tissues can be readily converted to L-arginine, thus raising plasma and tissue levels of L-arginine and enhancing NO production. Supplemental L-citrulline has promise as a therapeutic adjunct in disease states associated with L-arginine deficiencies.

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Integrity and stability of the citrulline–arginine pathway in normal and tumour cell lines

Cited by 27 publications

References 27 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

Canavanine augments proapoptotic effects of arginine deprivation in cultured human cancer cells

Therapeutic Use of Citrulline in Cardiovascular Disease

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