**8. Role of arginine deprived agents**

Deprivations of arginine from cancerous cells not only have a cytotoxic effect on cell but also induce specific cell cycle arrest. The cell cycle arrest analysis was done to check the surviving population of pancreatic and ovarian cancer cells to examine the consequence of arginine deprivation on cell cycle. The first reported arginine deprivation agent was ADI enzyme which degraded arginine and prevents cell growth s in culture from growing [63]. Human Arginase 1 (HuArgI) is second arginine deprivation agent and used to target arginine auxotrophic cancer cell lines and it is stable longer in serum, improved catalytic activity and less exposed with immune system [64]. Different types of cancerous cell lines undergo different mechanisms of cell death when deprived to arginine such as the process of autophagy, when cell degrades itself during nutrients limitation leads to starvation and cell death. Moreover, autophagy inhibited by HuArgI may indicate no caspase activation, no loss in membrane integrity and prevent the cell death caused by apoptosis [65].

#### **9. In inhibition of cell migration**

Cell migration is a well accepted attribute of the cancerous cell and arginine depletion majorly affect on cell viability and migration [66]. Low level of arginine

*Bioactive Compounds - Biosynthesis, Characterization and Applications*

remains the center of interest among the cancer researchers [55].

**7. ADI obstructed the angiogenetic activity**

of auxotrophic cells. [59]. Induction of apoptosis

synthetase-deficient cells, pinpointing the reduction in catabolism and increase the expression of polyamine biosynthetic enzymes. This metabolic reprogramming elucidates a synthetic lethal interaction between arginosuccinate synthetase loss and polyamine metabolism, which could potentially be exploited for the treatment of arginosuccinate synthetase-negative cancers [54]. The reason for down-regulation of arginosuccinate synthetase in cancer cells is not cleared properly but always

The enzyme ADI inhibits the tumor growth not only by depletion of arginine but also by suppression the angiogenic activity via less NO production [20] as shown **Figure 6**. ADI has an also strong capability to deplete arginine from plasma and inhibit NO production which resulting an effective inhibitory role of ADI in NO-mediated angiogenesis [56]. During in vitro study, the anti-angiogenic activity of ADI to inhibit micro vessel tube formation and migration in endothelial cell cultures was reported by Beloussow et al. [57]. Arginine depletion with the treatment of ADI enzyme also alters the level of proline, polyamines, glutamate and succinate. Polyamines are essential for tumor proliferation and their less production directly affects angiogenesis. Mycoplasma-derived ADI-PEG20 is majorly focused and most commonly used as a potential therapeutic agent for clinical investigation with different anti-neoplastic activity [58]. Mechanistically, ADI is capable of inhibiting the metabolic activity of cancerous cells and take parts in autophagy and apoptosis

Arginine limitation has also been recorded to induce apoptosis which leads cell death in ASS1-negative tumor [60]. Even though, the signaling pathway for apoptosis is not clear yet, but it has been reported that apoptosis induced by arginine deprivation can be activated via caspase-dependent/independent pathways [1]. The limitation of arginine in ASS1-negative mesothelioma cells induced apoptosis via

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**Figure 6.**

*Role of nitric oxide for angiogenesis and cancer proliferation and migration.*

**Figure 8.** *Migration and proliferation of cancer.*

accompany with the down-regulation of ASS1 expression which may leads the complete auxotrophic and mitigation of cancer cell migration [67]. The migration dependent on arginine requires optimum arginine to be catabolized two specific major enzymes nitric oxide synthase and arginase1 and produced citrulline and NO [68]. This increased level of promotes the cell viability, proliferation and migration during the process of wound healing [69]. Higher level of NO also activates signaling of focal adhesion kinase (FAK) cascade, which take parts in integrin assembly and disassembly as shown in **Figure 8**. Less arginine degradation to NO during wound healing showed a decrease in migration of colorectal cancer cells and added citrulline restored cell migration [70]. This higher nitric oxide synthase activity was recorded in intestinal epithelial cells in the presence of arginine and citrulline and NO production, which directly stimulate the cell migration [71]. The impact of arginine limitation and role of FAK was noticed when a study done on human intestinal epithelial cells which showed a significant role of NO production and cell migration [72]. Similar to this, other enzyme such as ornithine decarboxylase (ODC) used in polyamine biosynthesis also play important role in cell migration where polyamines increase the K+ channel mediated Ca2+ influx and support to FAK activation [73]. The inhibition of ODC enzymes was majorly correlated with abnormal morphology of actin-cytoskeleton of metastatic cells migration [74]. Other signals including PI3K, Rho GTPases, microtubules and integrins always found to be interlinked and positive play important role in cell polarity by regulating intracellular junctions, cell adhesion, invasion and migration [75]. Arginine depletion also hamper the RhoA activation in colorectal cancer cells and during a report, the increased level of NO was majorly found to be involved in the RhoA activation in pancreatic cancer cells [76].

### **10. Conclusion**

Several cancerous cells exhibited a higher metabolic requirement for specific amino acids to meet their rapid growth and migration. Therefore, specific amino

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India

**Author details**

Kapil Singh Narayan1

\* and Reenu Kashyap2

\*Address all correspondence to: kapilnsnk@gmail.com

provided the original work is properly cited.

1 New Bolton Center, University of Pennsylvania, Kennett Square, PA, USA

2 Dairy Microbiology Division, National Dairy Research Institute, Karnal, Haryana,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Arginine Metabolism: An Enlightening Therapeutic Attribute for Cancer Treatment*

acid limitation could be a novel therapy target to cure cancer. Arginine is a well known essential amino acid with the ability to regulate cellular activities and influence viability, proliferation, motility, migration, adhesion and invasion. There are several clinical studies have been reported which clearly explain the impact of arginine limitation as a therapy to cure arginine auxotrophic tumors and arginine converted in to polyamines and NO, majorly focused for cell proliferation and migration. The role of ADI enzyme and less expression of ASS1 gene was found to be directly correlated with the production of NO and polyamines and elimination of arginine auxotrophic tumors. Some tumors such as hepatocellular carcinoma and melanoma are found to be very sensitive for this treatment of arginine limitation because here arginine does not take parts in the urea cycle. Thus, the development of a new drug and drug resistance due to induction of ASS1 expression leads to a potential problem in tumors curing. Overall, the complete mechanism understanding of arginine limitation and inhibition of arginine auxotrophic cancer cell proliferation and migration is not clear and still further investigation is required to

*DOI: http://dx.doi.org/10.5772/intechopen.97254*

understand this cancer therapy.

#### *Arginine Metabolism: An Enlightening Therapeutic Attribute for Cancer Treatment DOI: http://dx.doi.org/10.5772/intechopen.97254*

acid limitation could be a novel therapy target to cure cancer. Arginine is a well known essential amino acid with the ability to regulate cellular activities and influence viability, proliferation, motility, migration, adhesion and invasion. There are several clinical studies have been reported which clearly explain the impact of arginine limitation as a therapy to cure arginine auxotrophic tumors and arginine converted in to polyamines and NO, majorly focused for cell proliferation and migration. The role of ADI enzyme and less expression of ASS1 gene was found to be directly correlated with the production of NO and polyamines and elimination of arginine auxotrophic tumors. Some tumors such as hepatocellular carcinoma and melanoma are found to be very sensitive for this treatment of arginine limitation because here arginine does not take parts in the urea cycle. Thus, the development of a new drug and drug resistance due to induction of ASS1 expression leads to a potential problem in tumors curing. Overall, the complete mechanism understanding of arginine limitation and inhibition of arginine auxotrophic cancer cell proliferation and migration is not clear and still further investigation is required to understand this cancer therapy.
