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

Cheng, Paul; Lam, Alan Tin-Lun; Lam, Wing; Tsui, S. M.; Cheng, Anthony Wai Ming; Lo, Wai Hung; Leung, Yun Chung

doi:10.1158/0008-5472.can-06-1945

Cited by 269 publications

(306 citation statements)

References 31 publications

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“…Interestingly, O-ASCs secrete arginine under arginine-deprivation conditions and this secreted arginine was uptaken by cancer cells, thereby increases NO synthesis and cancer cells' growth rate. Arginine depletion is currently used as a therapy for melanoma and hepatocellular carcinoma (31,32). We showed that when O-ASC-secreted arginine is depleted (using L-arginase) or when O-ASC-secreted factors induced increased NO synthesis in cancer cells is inhibited (using L-NAME), there is a decline in the growth rate of both ovarian cancer and endometrial cancer cells.…”

Section: Discussionmentioning

confidence: 92%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using N G -nitro-L-arginine methyl ester (L-NAME), we demonstrate that patientderived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASCsecreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASCmediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment-secreted factors using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Cancer Res; 75(2); 456-71. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 92%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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“…However, recently Cheng et al have studied 5 HCC cell lines (HepG2, Hep3B, PLC/PRF/5, Huh7 and Sk-HEP-1) and reported that these cell lines express ASS and are not sensitive to ADI [30]. On the other hand, these cell lines lack OCT expression and are sensitive to arginase [30].…”

Section: Antitumor Activity Of Adi-peg20 In Hepatocellular Carcinomamentioning

confidence: 99%

“…These drawbacks may explain why the development of arginase as an antitumor agent has failed despite its activity seen in vitro [28,29]. Nevertheless, recently pegylated arginase has been shown to have activity in hepatocellular carcinoma both in vitro and in vivo due to lack of OCT expression in certain hepatocellular carcinoma cell lines [30]. On the other hand, arginine deiminase, a microbial enzyme from mycoplasma which catabolizes arginine to citrulline and ammonia, is more attractive due to the fact that tumor cells which lack ASS will not be able to synthesize intracellular arginine from citrulline while normal cells are able to regenerate arginine.…”

Section: Introductionmentioning

confidence: 99%

Arginine Deprivation as a Targeted Therapy for Cancer

Feun

You

et al. 2008

CPD

196

188

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Certain cancers may be auxotrophic for a particular amino acid and amino acid deprivation is one method to treat these tumors. Arginine deprivation is a novel approach to target tumors which lack argininosuccinate synthetase (ASS) expression. ASS is a key enzyme which converts citrulline to arginine. Tumors which usually do not express ASS include melanoma, hepatocellular carcinoma, some mesotheliomas and some renal cell cancers. Arginine can be degraded by several enzymes including arginine deiminase (ADI). Although ADI is a microbial enzyme from mycoplasma, it has high affinity to arginine and catalyzes arginine to citrulline and ammonia. Citrulline can be recycled back to arginine in normal cells which express ASS, whereas ASS(−) tumor cells cannot. A pegylated form of ADI (ADI-PEG20) has been formulated and has shown in vitro and in vivo activity against melanoma and hepatocellular carcinoma. ADI-PEG20 induces apoptosis in melanoma cell lines. However, arginine deprivation can also induce ASS expression in certain melanoma cell lines which can lead to in-vitro drug resistance. Phase I and II clinical trials with ADI-PEG20 have been conducted in patients with melanoma and hepatocellular carcinoma and antitumor activity has been demonstrated in both cancers. This article reviews our laboratory and clinical experience as well as others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.

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“…In conclusion, rhArg demonstrates a promising novel agent for prostate cancer treatment (Cheng et al, 2007).…”

Section: Recombinant Human Arginase (Rharg)mentioning

confidence: 86%

“…Recombinant human arginase (rhArg) demonstrated significant cytotoxicity in hepatocellular carcinoma and melanoma, in vitro and in vivo (Cheng et al, 2007;Lam et al, 2009;Lam et al, 2010). In contrast to ADI-PEG20, the sensitivity to rhArg in hepatocellular carcinoma and melanoma is independent of ASS expression.…”

Section: Recombinant Human Arginase (Rharg)mentioning

confidence: 99%

Arginine enzymatic deprivation and diet restriction for cancer treatment

Zam

2017

Braz. J. Pharm. Sci.

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Recent findings in amino acid metabolism and the differences between normal, healthy cells and neoplastic cells have revealed that targeting single amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. Arginine is derived from dietary protein intake, body protein breakdown, or endogenous de novo arginine production and several studies have revealed disturbances in its synthesis and metabolism which could enhance or inhibit tumor cell growth. Consequently, there has been an increased interest in the arginine-depleting enzymes and dietary deprivation of arginine and its precursors as a potential antineoplastic therapy. This review outlines the most recent advances in targeting arginine metabolic pathways in cancer therapy and the different chemo-and radio-therapeutic approaches to be co-applied.

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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

Abstract: Hepatocellular carcinoma (HCC)

Cited by 269 publications

References 31 publications

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

Arginine Deprivation as a Targeted Therapy for Cancer

Arginine enzymatic deprivation and diet restriction for cancer treatment

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