Arginine enzymatic deprivation and diet restriction for cancer treatment

Zam, Wissam

doi:10.1590/s2175-97902017000300200

Cited by 8 publications

(5 citation statements)

References 57 publications

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“…Dietary arginine is not required by healthy subjects and is conditionally indispensable only for severely stressed patients (52). While protein restricted diets have been inhibitory for tumor growth in some mouse models of cancer (53), dietary depletion of arginine, certainly for the length of time that would be required in a patient with PKD, is likely not feasible since this amino acid is, of course, found in many proteins. However, enzymatic methods to specifically target arginine have been used in multiple clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis

Trott

Hwang

Ishimaru

et al. 2018

American Journal of Physiology-Renal Physiology

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Research into metabolic reprogramming in cancer has become commonplace, yet this area of research has only recently come of age in nephrology. In light of the parallels between cancer and autosomal dominant polycystic kidney disease (ADPKD), the latter is currently being studied as a metabolic disease. In clear cell renal cell carcinoma (RCC), which is now considered a metabolic disease, we and others have shown derangements in the enzyme arginosuccinate synthase 1 (ASS1), resulting in RCC cells becoming auxotrophic for arginine and leading to a new therapeutic paradigm involving reducing extracellular arginine. Based on our earlier finding that glutamine pathways are reprogrammed in ARPKD, and given the connection between arginine and glutamine synthetic pathways via citrulline, we investigated the possibility of arginine reprogramming in ADPKD. We now show that, in a remarkable parallel to RCC, ASS1 expression is reduced in murine and human ADPKD, and arginine depletion results in a dose-dependent compensatory increase in ASS1 levels as well as decreased cystogenesis in vitro and ex vivo with minimal toxicity to normal cells. Nontargeted metabolomics analysis of mouse kidney cell lines grown in arginine-deficient versus arginine-replete media suggests arginine-dependent alterations in the glutamine and proline pathways. Thus, depletion of this conditionally essential amino acid by dietary or pharmacological means, such as with arginine-degrading enzymes, may be a novel treatment for this disease.

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Section: Discussionmentioning

confidence: 99%

Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis

Trott

Hwang

Ishimaru

et al. 2018

American Journal of Physiology-Renal Physiology

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“…To exploit this metabolic deficiency, multiple arginine destruction enzymes have been developed, including arginase, arginine decarboxylase, and arginine deiminase 1,11 . The most clinically relevant is PEGylated arginine deiminase (ADI-PEG20), which is currently in clinical trials 12 .…”

Section: Introductionmentioning

confidence: 99%

Systems level profiling of arginine starvation reveals MYC and ERK adaptive metabolic reprogramming

et al. 2020

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Arginine auxotrophy due to the silencing of argininosuccinate synthetase 1 (ASS1) occurs in many carcinomas and in the majority of sarcomas. Arginine deiminase (ADI-PEG20) therapy exploits this metabolic vulnerability by depleting extracellular arginine, causing arginine starvation. ASS1-negative cells develop resistance to ADI-PEG20 through a metabolic adaptation that includes re-expressing ASS1. As arginine-based multiagent therapies are being developed, further characterization of the changes induced by arginine starvation is needed. In order to develop a systems-level understanding of these changes, activity-based proteomic profiling (ABPP) and phosphoproteomic profiling were performed before and after ADI-PEG20 treatment in ADI-PEG20-sensitive and resistant sarcoma cells. When integrated with metabolomic profiling, this multi-omic analysis reveals that cellular response to arginine starvation is mediated by adaptive ERK signaling and activation of the Myc-Max transcriptional network. Concomitantly, these data elucidate proteomic changes that facilitate oxaloacetate production by enhancing glutamine and pyruvate anaplerosis and altering lipid metabolism to recycle citrate for oxidative glutaminolysis. Based on the complexity of metabolic and cellular signaling interactions, these multi-omic approaches could provide valuable tools for evaluating response to metabolically targeted therapies.

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“…L-Asparaginase (L-ASNase) catalyzes the hydrolysis of asparagine, enzymes such as arginine deiminase and arginine decarboxylase are involved in arginine catabolism. These enzymes result in deprivation of the amino acids required in protein synthesis and subsequently cause tumor cell death [ 23 ].…”

Section: Mechanism Of Tumor Suppressionmentioning

confidence: 99%

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

Sawant

Patil

Gupta

et al. 2020

IJMS

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Conventional anti-cancer therapy involves the use of chemical chemotherapeutics and radiation and are often non-specific in action. The development of drug resistance and the inability of the drug to penetrate the tumor cells has been a major pitfall in current treatment. This has led to the investigation of alternative anti-tumor therapeutics possessing greater specificity and efficacy. There is a significant interest in exploring the use of microbes as potential anti-cancer medicines. The inherent tropism of the bacteria for hypoxic tumor environment and its ability to be genetically engineered as a vector for gene and drug therapy has led to the development of bacteria as a potential weapon against cancer. In this review, we will introduce bacterial anti-cancer therapy with an emphasis on the various mechanisms involved in tumor targeting and tumor suppression. The bacteriotherapy approaches in conjunction with the conventional cancer therapy can be effective in designing novel cancer therapies. We focus on the current progress achieved in bacterial cancer therapies that show potential in advancing existing cancer treatment options and help attain positive clinical outcomes with minimal systemic side-effects.

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Arginine enzymatic deprivation and diet restriction for cancer treatment

Cited by 8 publications

References 57 publications

Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis

Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis

Systems level profiling of arginine starvation reveals MYC and ERK adaptive metabolic reprogramming

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

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