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ÀÇÇоàÇР ¾çº´Âù (2019-11-08 09:10)

 
Chemical structure of 6-diazo-5-oxo-l-norleucine (DON) and the prodrug JHU-083 (Ethyl 2-(2-Amino-4-methylpentanamido)-DON). / £À sciencedirect.com(Âü°í 1)

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Glutamic acid as anticancer agent: An overview
-- Satyajit Dutta,a Supratim Ray,b,⁎ and K. Nagarajanc
-- Saudi Pharm J. 2013 Oct; 21(4): 337–343.

Abstract
The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. It also possesses anticancer activity. So the transportation and metabolism of glutamine are also discussed for better understanding the role of glutamic acid. Glutamates are the carboxylate anions and salts of glutamic acid. Here the roles of various enzymes required for the metabolism of glutamates are also discussed.


1. Introduction
In Cancer mostly there is depletion of glutamine, as cancer cells consume glutamine at large scale that is why there is lack of glutamine in the skeletal muscle (Kulkarni et al., 2005). Glutamine plays very important roles in tumor cell. Firstly it acts as a nitrogen donor in the nucleotide and amino acid biosynthesis, secondly glutamine helps in the uptake of essential amino acid and it maintains the activation of TOR kinase (Wise and Thompson, 2010). In many cancer cells, glutamine is the primary mitochondrial substrate and it maintains mitochondrial membrane potential and integrity. It provides support for the NADPH production needed for redox control and macromolecular synthesis. Glutamine is the respiratory fuel of tumor cells. Glutamic acid and glutamine both are inter convertible. Glutamic acid comes under the major group of neurotransmitters. It is the major work horse neurotransmitter of the brain. It increases the brain function and mental activity. It detoxifies the brain from ammonia by attaching itself to nitrogen atoms in the brain and also helps in the transportation of potassium across the blood–brain barrier. It is conjectured that glutamate is involved in cognitive functions like learning and memory in the brain, though excessive amounts may cause neuronal damage associated with diseases like amyotrophic lateral sclerosis, lathyrism and Alzheimer¡¯s disease (Dutta et al., 2011).

2. Glutamic acid as anticancer agent

l-Glutamic acid is converted into l-glutamine by l-glutamine synthetase. l-glutamine biosynthesize purines and pyrimidines by contributing 3- and 9-nitrogen groups of purine bases, 2-amino group of guanine, 3-nitrogen group and amino group of cytosine which are the bases of DNA and RNA (Dewald and Moore, 1958). l-Glutamine cannot be synthesized in neoplastic cells due to the lower reactivity of l-glutamine synthetase. Thus an antagonist of this enzyme can interfere with the metabolic process of l-glutamine and act as anticancer agents (Luzzio et al., 2000). Patients of cancer often develop glutamine depletion in the muscles due to uptake by tumors and chronic protein metabolism. On the basis of these, it can be assumed that structural variants of glutamine might possess possible antitumor activity.
l-Glutamic acid-¥ã-(4-hydroxyanilide) is isolated from mushroom Agaricus bisporous. It acts as a growth regulatory substance for inhibiting the B16 melanoma cells in culture (Srikanth et al., 2002). Azaserine and 6-diaza-5-oxo-l-norleucine antagonized the metabolic process involving l-glutamine and exhibited antitumor activity in animal models (Vishwanathan et al., 2008). An aryl amide derivative of l-threo-¥ã-hydroxy glutamic acid which is isolated from Justica ghiesbreghtiana is active against various tumors (Nishiyama et al., 2001). The synthetic amides of l-glutamic acid exhibit activity against Ehrlich ascites carcinoma (Vila et al., 1990). Four N-(benzenesulfonyl)-l-glutamic acid bis(p-substituted phenylhydrazides) have anticancer activity against PC-3 prostate cancer and in COLO-205 colon cancer. l-Glutamic acid-¥ã-monohydroxamate (GAH) demonstrated complete cytotoxicity against L-1210 cells in the culture and marked antitumoral activity in vivo against L-1210 leukemia and B-16 melanoma (Xu et al., 2005). Glutamate receptor is another important player in hippocampal long-term potentiation and memory. Glutamic acid, a glutamate receptor agonist enhances retention of memory (Cui et al., 2009). Glutamic acid is also useful in lowering blood pressure. According to a study by the Imperial College of London, people who consume more glutamic acid have low blood pressure than those who consume less (Stamler et al., 2009). When the glutamine importer SLC1A5 is impaired then the uptake of essential amino acids is also impaired and without the aid of essential amino acids rapamycin-sensitive mTORC1 is not activated. mTORC1 is responsible for the regulation of cell growth, protein translation and plays an important role in inhibiting macro autophagy (Nicklin et al., 2009). That means if mTORC1 is inactivated then there will be no cell growth and no protein translation. In glioblastoma cells, metabolism of glutamine provides the bulk of oxaloacetic acid (OAA) cellular pool (DeBerardinis et al., 2007). This OAA is one of the substrates in mitochondria that leads to the synthesis of many essential biological macromolecules like cholesterol (Hatzivassiliou et al., 2005). Hence glutamine is the primary substrate in cancer cells that provides precursor molecules to mitochondria for anaplerosis (replenishment of the carbon pool). c-MYC (Myc), a DNA transcription factor regulates three out of the five steps of purine and pyrimidine synthesis at oncogenic level. It also promotes glutaminolysis and this catabolism of glutamine leads to the larger amount of carbon in the cell, which allows the cell to produce more NADPH (Wise and Thompson, 2010). Since cancer cells depend on glutamine lack of glutamine can lead to the death of cancer cells. But as it is also required for some other essential functions in the body such as in the brain therefore that treatment should be adopted which can reduce the ability of the cell to uptake glutamine by targeting Myc and other proteins that are responsible for transporting glutamine into the cell. l-¥ã-Glutamyl-p-nitroanilide (GPNA) which inhibits SLC1A5 (Esslinger et al., 2005) and BCH (2-aminobicyclo-(2,2,1)heptanes carbozylic acid) which blocks mTORC1 (Nicklin et al., 2009) and that treatment which reprograms the mitochondria so that it no longer depends on glutamine can also be effective, e.g. amino-oxyacetic acid (AOA) is used because it is a transaminase inhibitor (Moreadith and Lehninger, 1984).


3. Glutamic acid as conjugates with anticancer drug
Glutamic acid is used as a conjugate because it increases the efficacy of anticancer drug and decreases its toxicity toward normal cells. Polyglutamic acid is biodegradable, edible and nontoxic toward humans (Shih et al., 2004).

3.1. Conjugate with All-trans retinoic acid (ATRA)
ATRA is an active metabolite of vitamin A. It is used in the treatment of acute promyelocytic leukemia and myelodysplastic syndrome. It has a slow dissolution rate and low bioavailability. Therefore to obtain ATRA with better solubility, transportation and bioavailability, derivatives of ATRA containing glutamic acid or its sodium salt were synthesized. The two derivatives of ATRA, RAE and RAENa, exhibited improved aqueous solubility and were more effective in mice bearing S(180) tumors (Cui et al., 2009).

3.2. Conjugate with paclitaxel
Conjugation of paclitaxel and the water-soluble polyglutamate is known as poly (l-glutamic acid)-paclitaxel (PG-TXL). Observations showed that PG-TXL has more antitumor activity than free paclitaxel. PG-TXL exerts its anticancer activity by the continuous release of free paclitaxel into cells (Oldham et al., 2000).

3.3. Conjugate with cisplatin
Cisplatin [cis-dichlorodiammineplatinum (II), CDDP] is combined with ¥ã-poly(¥á,l-glutamic acid) (¥ã-PGA) to form ¥ã-poly(¥á,l-glutamic acid)-cis-dichlorodiammineplatinum (¥ã-PGA-CDDP) which is water soluble. ¥ã-PGA–cisplastin conjugate effectively inhibits human breast tumor cells xenografted into nude mice. It also reduces the toxic side effects associated with the use of free CDDP and also produced desirable pharmacokinetics and enhanced antitumor activity (Ye et al., 2006) (Figure 1).


3.4. Conjugate with curcumin
Curcumin [diferuloylmethane; 1,7-bis-(4-hydroxyl-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the major pigmentary component of turmeric (Curcuma longa). Curcumin with nphthaloyl-glutamoylchloride forms 4,40-(di-o-glutamoyl)-curcumin. According to a study curcumindiglutamoyl derivative was found to be more potent against cancer cell lines, HeLa (cervical cancer) and KB (oral cancer), than other derivatives. It is due to the activation of caspases which is facilitated due to accumulation and better stability of diglutamiccurcumin (Dubey et al., 2008).

3.5. Conjugate with 20(s)-camptothecin (CPT)
Due to the instability of active lactone the therapeutic efficacy of 20(s)-camptothecin (CPT) is limited in humans. By binding one molecule of a drug via the ¥ã-carboxylic acid of each monomeric subunit of poly-(l-glutamic acid) (PGA) it leads to the stability of lactone. Linking of CPT to a high molecular weight anionic polymer that is PGA enhances solubility and improves distribution to the tumor through enhanced permeability and retention (EPR effect) (Singer et al., 2001).

3.6. Conjugate with N-(4-hydroxyphenyl)retinamide (4HPR)

Several studies have indicated that N-(4-hydroxyphenyl)retinamide (4HPR) treatment is associated with the inhibition of angiogenesis and a decreased vascular response in vitro and in vivo. 4HPR was bound to a synthetic polyamino acid, poly(l-glutamic acid) (PG). PG-4HPR was evaluated for its release kinetics and in vitro anti-proliferative and in vivo antitumor activities against ovarian cancer cell lines. It was confirmed that treatments with both 4HPR and PG-4HPR decreased the expression of pre-angiogenic factor VEGF in SKOV3 tumors. In-vivo, PG-4HPR demonstrated significantly enhanced antitumor activities compared to 4HPR in both early treatment and later treatment protocols. Treatments with PG-4HPR suppressed the expression of VEGF and reduced blood flow into the tumor (Zou et al., 2007).

4. Derivatives of glutamic acid as anticancer agent

4.1. Aminopteroylglutamic acid or pteroyl-l-glutamic acid

Aminopterin (4-aminopteroic acid), a 4-amino analog of folic acid, is an antineoplastic drug with immunosuppressive properties used in chemotherapy (Oaks et al., 2010). Folate is involved in DNA synthesis and methylation which may reduce breast cancer risk, particularly among women with greater alcohol consumption. High intake of folate may reduce the risk of colon cancer (Giovannucci et al., 1998), but the dosage and duration relations and the impact of diet compared with supplementary sources are not well understood (Boehm et al., 2009). Folate intake decreased the risk of pancreatic cancer in women but not in men (Percival et al., 2008).

4.2. Methotrexate

Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]-l-glutamic acid. Methotrexate tablets are used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T-cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate tablets are also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin¡¯s lymphomas. It reduces dihydrofolates to tetrahydrofolates by the help of enzyme dihydrofolic acid reductase which inhibits the synthesis of purines (Skeel, 2008).

4.3. l-Theanine

Chemically l-theanine is ¥ã-ethylamino-l-glutamic acid. Limited studies evaluate the effects of l-theanine in the prevention of cancer. The observed anticancer effects are largely attributed to the catechins found in tea, while action on tumors may be due to an enhanced immune response (McPhee et al., 2011).

4.4. Thalidomide

It is a chemotherapeutic agent used against multiple myeloma, myelodysplastic syndrome, leprosy etc. It acts by inhibiting VEGF, TNF-¥á, GI growth factor, proliferation of NK cells and stimulation of T-cells.