Arginine deprivation and autophagic cell death in cancer

Szlosarek, Peter W.

doi:10.1073/pnas.1416560111

Cited by 34 publications

(21 citation statements)

References 22 publications

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“…18, 23, 42 ADI-PEG20 treatment of prostate cancer is unique in that arginine starvation in these tumor cells causes chromatophagy, a form of autophagy in which cells start incorporating chromatin into autophagosomes, followed by cell death. 42, 43 In contrast, sarcoma cells are able to use sustained autophagy until they reprogram and re-express ASS1, a change that renders single-agent ADI-PEG20 treatment ineffective. However, this starvation primes the cells for induction of necroptosis because of the loss of anti-ripoptosome regulatory proteins, as well as caspase 3, a rate-limiting protein that initiates apoptosis.…”

Section: Discussionmentioning

confidence: 99%

A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas

et al. 2016

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Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact that no single gene mutation or alteration has been identified among the diverse histologic subtypes. We searched for therapeutically druggable targets that are common to a wide range of histologies and hence could provide alternatives to the conventional chemotherapy. Seven hundred samples comprising 45 separate histologies were examined. We found that almost 90% were arginine auxotrophs, as the expression of argininosuccinate synthetase 1 was lost or significantly reduced. Arginine auxotrophy confers sensitivity to arginine deprivation, leading temporarily to starvation and ultimately to cell survival or death under different circumstances. We showed that, in sarcoma, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. However, when starvation was simultaneously prolonged by ADI-PEG20 while inhibited by the clinically available drug chloroquine, sarcoma cells died via necroptosis and apoptosis. These results have revealed a novel metabolic vulnerability in sarcomas and provided the basis for a well-tolerated alternative treatment strategy, potentially applicable to up to 90% of the tumors, regardless of histology.

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Section: Discussionmentioning

confidence: 99%

A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas

et al. 2016

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“…The amino acid arginine, which was increased in plasma from PCa patients, is highly versatile and involved in several processes. Arginine and its products are critical for the growth of several cancers by enhancing tumour growth, and arginine depletors have been shown effective as anti-cancer drugs in several cancers including PCa ( Kim et al , 2009 ; Delage et al , 2010 ; Szlosarek, 2014 ). Further studies on a larger cohort are necessary to validate the findings of increased blood levels of certain amino acids, including arginine.…”

Section: Discussionmentioning

confidence: 99%

Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia

et al. 2015

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Background:An individualised risk-stratified screening for prostate cancer (PCa) would select the patients who will benefit from further investigations as well as therapy. Current detection methods suffer from low sensitivity and specificity, especially for separating PCa from benign prostatic conditions. We have investigated the use of metabolomics analyses of blood samples for separating PCa patients and controls with benign prostatic hyperplasia (BPH).Methods:Blood plasma and serum samples from 29 PCa patient and 21 controls with BPH were analysed by metabolomics analysis using magnetic resonance spectroscopy, mass spectrometry and gas chromatography. Differences in blood metabolic patterns were examined by multivariate and univariate statistics.Results:By combining results from different methodological platforms, PCa patients and controls were separated with a sensitivity and specificity of 81.5% and 75.2%, respectively.Conclusions:The combined analysis of serum and plasma samples by different metabolomics measurement techniques gave successful discrimination of PCa and controls, and provided metabolic markers and insight into the processes characteristic of PCa. Our results suggest changes in fatty acid (acylcarnitines), choline (glycerophospholipids) and amino acid metabolism (arginine) as markers for PCa compared with BPH.

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“…Arginine deprivation has also been reported to induce apoptosis and cause cell death in ASS-negative tumor cell lines, including human lymphoblastic cell lines, mesothelioma cells, melanoma cell lines, prostate cancer cell lines, and breast cancer [ 5 , 89 , 95 , 101 , 113 , 136 , 137 ]. Although the signaling pathway responsible for apoptosis is still not clear, it is recognized that the apoptosis induced by arginine deprivation could be activated via caspase-dependent and/or independent pathways [ 85 , 102 ].…”

Section: Arginine Metabolism and Cancer Therapymentioning

confidence: 99%

Arginine Metabolism in Bacterial Pathogenesis and Cancer Therapy

Xiong

Teng

Botelho

et al. 2016

IJMS

116

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Antibacterial resistance to infectious diseases is a significant global concern for health care organizations; along with aging populations and increasing cancer rates, it represents a great burden for government healthcare systems. Therefore, the development of therapies against bacterial infection and cancer is an important strategy for healthcare research. Pathogenic bacteria and cancer have developed a broad range of sophisticated strategies to survive or propagate inside a host and cause infection or spread disease. Bacteria can employ their own metabolism pathways to obtain nutrients from the host cells in order to survive. Similarly, cancer cells can dysregulate normal human cell metabolic pathways so that they can grow and spread. One common feature of the adaption and disruption of metabolic pathways observed in bacterial and cancer cell growth is amino acid pathways; these have recently been targeted as a novel approach to manage bacterial infections and cancer therapy. In particular, arginine metabolism has been illustrated to be important not only for bacterial pathogenesis but also for cancer therapy. Therefore, greater insights into arginine metabolism of pathogenic bacteria and cancer cells would provide possible targets for controlling of bacterial infection and cancer treatment. This review will summarize the recent progress on the relationship of arginine metabolism with bacterial pathogenesis and cancer therapy, with a particular focus on arginase and arginine deiminase pathways of arginine catabolism.

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Arginine deprivation and autophagic cell death in cancer

Cited by 34 publications

References 22 publications

A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas

A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas

Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia

Arginine Metabolism in Bacterial Pathogenesis and Cancer Therapy

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