**4. Impact of arginine degradation in cancer therapy**

Cancer cells need excess quantities of specific amino acids for their diverse metabolism rate for higher proliferation and become resist for some cell death signals. Identification of the metabolic dissimilarly between cancer cells and normal cells, cellular metabolism of cancer cells is a therapeutic target and focusing field of cancer research [40]. The deprivation of arginine inside cancer cells, which makes the cells auxotrophic, has been centered one of the novel approach for cancer treatment [22]. There are several targets have been reported which directly take part in cancer mitigation as discussed below;

## **5. Citrulline-NO cycle**

Citrulline is well known as a byproduct of NO synthetase enzyme and can be recycled to arginine by the key enzymes ASS1 and ASL. Both these enzymes are strongly expressed in liver and kidney then the other cells and tissues. The citrulline-nitric oxide cycle stimulates the activation of cytokines such as interferon (IFN) [41] and enhances the expression level of ASS1 enzyme as noticed in mouse microglial cells [42] and human tumor cell lines [43]. Impaired NO production from citrulline has been reported as a vital factor for the abnormal proliferation of keratinocytes in psoriasis epidermis. Higher arginase I with induced NO synthetase inhibits the keratinocyte proliferation by eliminating the arginine availability [44]. Enzymes for arginine metabolism are the potent therapeutic targets to control NO and cancerous cell proliferation as shown in **Figure 4**. In citrulline-NO pathway, NO is synthesized from arginine by the three nitric oxide synthase (NOS) isoforms; endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) and maintain the citrulline -NO cycle in the functional cells [45]. NOS and arginase1 use arginine as same substrate but arginase1 down-regulate because NO production by competing with NOS for arginine [46]. Remarkably, iNOS and arginase1 activities are reciprocally regulated in the cancerous cells by the involvement of cytokines and this can be guaranteed for the optimum production of NO but not in immunostimulated macrophages [47].

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**Figure 5.**

*ADI enzyme.*

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

The mechanisms which exhibited the loss of ASS1 activity are specifically depend on the type of cancerous cell and availability of arginine. ASS1 is a rate-limiting enzyme involved in arginine biosynthesis and has been investigated in numerous cancerous conditions such as melanoma [48], hepatocellular carcinoma [49] and pancreatic cancers [50], and the. ASS1-negative cancer cells are auxotrophic for arginine and exhibit sensitivity to arginine deprivation [51]. Cancerous cells have lack expression of ASS1 enzyme required for arginine biosynthesis which is an exogenous source for proteins synthesis and cellular growth [52]. Less ASS1 expression was recorded as a biomarker in cancer cell and for overall cellular functioning. The ASS1-deficient cancers with arginine auxotrophy have been initiated as the development of therapeutics by depriving arginine through degradation and trigger the apoptosis in arginine auxotrophic cancerous cells [53] as shown in **Figure 5**. The low levels of acetylated polyamine metabolites were found in arginosuccinate

*Impact of gene ASS1 expression for cancer progression and proliferation and its down-regulation by* 

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

**6. Inhibition of ASS1 activity**

*Role of nitric oxide for tumor alimination.*

**Figure 4.**

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

**Figure 4.** *Role of nitric oxide for tumor alimination.*

*Bioactive Compounds - Biosynthesis, Characterization and Applications*

response elements (cre) located in the promoter regions [20].

**4. Impact of arginine degradation in cancer therapy**

cancer mitigation as discussed below;

**5. Citrulline-NO cycle**

timulated macrophages [47].

Cancer cells need excess quantities of specific amino acids for their diverse metabolism rate for higher proliferation and become resist for some cell death signals. Identification of the metabolic dissimilarly between cancer cells and normal cells, cellular metabolism of cancer cells is a therapeutic target and focusing field of cancer research [40]. The deprivation of arginine inside cancer cells, which makes the cells auxotrophic, has been centered one of the novel approach for cancer treatment [22]. There are several targets have been reported which directly take part in

Citrulline is well known as a byproduct of NO synthetase enzyme and can be recycled to arginine by the key enzymes ASS1 and ASL. Both these enzymes are strongly expressed in liver and kidney then the other cells and tissues. The citrulline-nitric oxide cycle stimulates the activation of cytokines such as interferon (IFN) [41] and enhances the expression level of ASS1 enzyme as noticed in mouse microglial cells [42] and human tumor cell lines [43]. Impaired NO production from citrulline has been reported as a vital factor for the abnormal proliferation of keratinocytes in psoriasis epidermis. Higher arginase I with induced NO synthetase inhibits the keratinocyte proliferation by eliminating the arginine availability [44]. Enzymes for arginine metabolism are the potent therapeutic targets to control NO and cancerous cell proliferation as shown in **Figure 4**. In citrulline-NO pathway, NO is synthesized from arginine by the three nitric oxide synthase (NOS) isoforms; endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) and maintain the citrulline -NO cycle in the functional cells [45]. NOS and arginase1 use arginine as same substrate but arginase1 down-regulate because NO production by competing with NOS for arginine [46]. Remarkably, iNOS and arginase1 activities are reciprocally regulated in the cancerous cells by the involvement of cytokines and this can be guaranteed for the optimum production of NO but not in immunos-

in several lactic acid bacteria (LAB), *bacilli, clostridia, pseudomonads, aeromonads, mycoplasmas, halobacteria, and cyanobacteria* [36]. ADI pathway is completed by three key enzymes: arginine deiminase (ADI), ornithine transcarbamoylase (OTC), and carbamate kinase (CK) as shown in **Figure 3**. Moreover, in *Pseudomonas aeruginosa*, a fourth gene that encodes a transport protein to exchange arginine and ornithine for this pathway has been identified [37]. ADI pathway is most important for the bacterial cell survival in the acidic environmental condition because arginine degradation by ADI pathway produced ammonia that raises the cytoplasmic and extracellular pH and produced ATP use as the energy source for cell survival. In the absence of carbohydrate bacteria preferred arginine and utilize it by ADI pathway as an alternate energy source to engender energy for cellular growth [20, 38]. ADI pathway is regulated at transcriptional level and regulated by transcriptional regulator ArgR [3, 37]. Moreover, carbon catabolite repression (CCR) has also been confirmed for the expression of ADI pathway in various bacteria. CCR regulates the expression of arc operon with glucose and catabolite control protein A (CcpA) [39]. CcpA is a transcriptional regulators belonging to the Crp/Fnr family and regulates the expression by the binding with regulatory proteins to the cis-acting catabolite

**158**
