Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer

Daylami, Rouzbeh; Muilenburg, Diego J.; Virudachalam, Subbulakshmi; Bold, Richard J.

doi:10.1186/s13046-014-0102-9

Cited by 35 publications

(30 citation statements)

References 32 publications

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“…Previous work has identified changes in the GEM pathway that occur as a result of arginine starvation induced by ADI-PEG20 (12,44,45). This study confirmed that the degradation of arginine from ASS1-deficient, arginine auxotrophic cancers stabilizes c-Myc (19), and that the addition of DTX facilitates c-Myc translocation to the nucleus, which results in increased hENT1 surface expression.…”

Section: Discussionsupporting

confidence: 78%

“…Effect of acute and chronic arginine starvation on the GEM pathway in ASS1 À cell lines Based on previous findings, alterations in the pyrimidine pathway have been seen in response to arginine starvation (12,44,45). Using our established model of arginine starvation in sarcoma of acute and long-term ADI-PEG20 treated (LTAT), the alterations in the GEM pathway were examined ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Prudner

Rathore

Robinson

et al. 2019

Clinical Cancer Research

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Purpose: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1 À tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines.Experimental Design: ASS1 À tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1 þ ) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX.Results: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM: DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma.Conclusions: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Prudner

Rathore

Robinson

et al. 2019

Clinical Cancer Research

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“…Autophagy inhibitor chlorquine accelerated ADI-PEG20 induced cell death in vitro Pancreatic cancer 1. Inhibited growth and induced apoptosis of ASS1-ve pancreatic cancer cell lines in vitro (about 80% pancreatic cancer samples tested in the study were ASS1-ve) [ 166 , 167 ] 2. Suppressed growth of subcutaneously implanted tumor in athymic nude mice.…”

Section: Arginine Starvation As An Anti-cancer Strategymentioning

confidence: 99%

Drug-induced amino acid deprivation as strategy for cancer therapy

2017

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Cancer is caused by uncontrollable growth of neoplastic cells, leading to invasion of adjacent and distant tissues resulting in death. Cancer cells have specific nutrient(s) auxotrophy and have a much higher nutrient demand compared to normal tissues. Therefore, different metabolic inhibitors or nutrient-depleting enzymes have been tested for their anti-cancer activities. We review recent available laboratory and clinical data on using various specific amino acid metabolic pathways inhibitors in treating cancers. Our focus is on glutamine, asparagine, and arginine starvation. These three amino acids are chosen due to their better scientific evidence compared to other related approaches in cancer treatment. Amino acid-specific depleting enzymes have been adopted in different standard chemotherapy protocols. Glutamine starvation by glutaminase inhibitior, transporter inhibitor, or glutamine depletion has shown to have significant anti-cancer effect in pre-clinical studies. Currently, glutaminase inhibitor is under clinical trial for testing anti-cancer efficacy. Clinical data suggests that asparagine depletion is effective in treating hematologic malignancies even as a single agent. On the other hand, arginine depletion has lower toxicity profile and can effectively reduce the level of pro-cancer biochemicals in patients as shown by ours and others’ data. This supports the clinical use of arginine depletion as anti-cancer therapy but its exact efficacy in various cancers requires further investigation. However, clinical application of these enzymes is usually hindered by common problems including allergy to these foreign proteins, off-target cytotoxicity, short half-life and rapidly emerging chemoresistance. There have been efforts to overcome these problems by modifying the drugs in different ways to circumvent these hindrance such as (1) isolate human native enzymes to reduce allergy, (2) isolate enzyme isoforms with higher specificities and efficiencies, (3) pegylate the enzymes to reduce allergy and prolong the half-lives, and (4) design drug combinations protocols to enhance the efficacy of chemotherapy by drug synergy and minimizing resistance. These improvements can potentially lead to the development of more effective anti-cancer treatment with less adverse effects and higher therapeutic efficacy.

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“…The fundamental difference of cell cycle modulations in normal and malignant cells should be exploitable as a means of selective demise of tumor cells and ADI, in combination with other anti-cancer chemotherapeutic agents, which can be a potential strategy to improve chemosensitization against tumor cells. 115–118 …”

Section: Arginine Deiminasementioning

confidence: 99%

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

et al. 2016

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Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities.

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Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer

Cited by 35 publications

References 32 publications

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Drug-induced amino acid deprivation as strategy for cancer therapy

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

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