**7. ADI obstructed the angiogenetic activity**

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 of auxotrophic cells. [59].

Induction of 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

**161**

**Figure 7.**

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

mitochondrial inner membrane depolarization and Bcl-2-associated X protein (BAX) activation which is well known as program type II or caspase-independent cell death [55]. It was also reported that ASS1-deficient cancer cells, prolonged autophagy activated upon ADI treatment and impaired mitochondrial functions by inducing oxidative stress, chromatin autophagy and DNA leakage which finally causes cell death [61] as presented in **Figure 7**. In addition to this arginine limitation by pegylated (PEG) arginase causes cell death induced by necrosis as observed in acute myeloid leukemia (AML). In contrast, cell cycle arrest in AML cells did not induce cell apoptosis,

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].

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

autophagy, and rapid production of reactive oxygen species [62].

**8. Role of arginine deprived agents**

*Impact of ADI enzyme which leads the apoptosis in cancer cell.*

**9. In inhibition of cell migration**

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

#### **Figure 6.** *Role of nitric oxide for angiogenesis and cancer proliferation and migration.*

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

**Figure 7.** *Impact of ADI enzyme which leads the apoptosis in cancer cell.*

mitochondrial inner membrane depolarization and Bcl-2-associated X protein (BAX) activation which is well known as program type II or caspase-independent cell death [55]. It was also reported that ASS1-deficient cancer cells, prolonged autophagy activated upon ADI treatment and impaired mitochondrial functions by inducing oxidative stress, chromatin autophagy and DNA leakage which finally causes cell death [61] as presented in **Figure 7**. In addition to this arginine limitation by pegylated (PEG) arginase causes cell death induced by necrosis as observed in acute myeloid leukemia (AML). In contrast, cell cycle arrest in AML cells did not induce cell apoptosis, autophagy, and rapid production of reactive oxygen species [62].
