BARBARA CICERO 22/02/2013
GARLIC AND CANCER
INTRODUCTION
The health benefits of garlic extracts could be attributed to phytochemicals, which are produced during the extraction process, such as S-allylcysteine, S-allylmercaptocysteine, N-alfa-fructosyl arginine. When garlic is damaged or crushed the sulphur components are transformed in different organosulfur compounds. Enzymes in garlic will convert alliin into allicin, which has antimicrobial action. Allicin is not very stable, so it will have no biological effect when ingested by humans. Even when large quantities are consumed no allicin is detectable either in the serum or urine. (Intake of garlic and its bioactive components. 2001)
Health benefits of garlic and other Allium vegetables (e.g., onions), such as lipid lowering and anticancer effects, are credited to metabolic byproducts sulfur-containing (generated chewing and cutting these edible plants) and including Allicin and Diallyl trisulfide (DATS).Diallyl trisulfide , it is one of the principal components of the distilled oil of garlic. It is a iellowish liquid which is insoluable in water and has a strong garlic odor. It is produced during the decompositoin of allicin, which is released from garlic and otehr plants of the Aliaceae family A number of studies have indicated that the number of sulfur atoms on allyl sulfides determines their efficacy and biological activity, such as anticancer and anti-inflammatory effects. ( Molecular mechanisms of garlic-derived allyl sulfides in the inhibition of skin cancer progression.2012)
Garlic constituents have been studied extensively, and various derivatives of garlic were reported to inhibit the growth of several cancer cell types.
CANCER AND CARCINOGENESIS (Carcinogenesis)
Cancer is a genetic disease that consists of uncontrolled cell division. Genes that regulate cell growth must be damaged. Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. A series of mutations to these genes is required before a normal cell transforms into a cancer cell. Mutations to these genes provide the signals for tumor cells to start dividing uncontrollably. The activation of anaerobic glycolysis (the Warburg effect), which is not necessarily induced by mutations in proto-oncogenes and tumor suppressor genes, provides most of the building blocks required to duplicate the cellular components of a dividing cell and also the loss of the ability to go in apoptosis in essential for carcinogenesis.
The most desirable approach to treat cancer would be to identify the molecular signals that induce growth arrest and trigger terminal differentiation of cancerous cells. Existing evidence suggests that pomegranate pericarp, garlic, and onion oils promote differentiation of prostate cancer and leukemic cells, respectively. Hirsch et al. (Effect of purified allicin, the major ingredient of freshly crushed garlic, on cancer cell proliferation. 2000) reported that pure allicin, a major water-soluble chemical constituent of garlic, as well as aqueous extracts of garlic (with a similar concentration of allicin content) exhibited similar growth inhibitory potency, suggesting that garlic’s growth inhibitory properties are attributed to the water-soluble constituent, allicin. Accordingly, it is possible that allicin, present in the fresh garlic extracts, contributed to the altered morphology and growth reduction. However, the specific mechanism of differentiation and the crucial molecular markers have not been identified.
You et al (Allium vegetables and reduced risk of stomach cancer.2012) studied the association of Allium vegetable intake with the risk of gastric cancer in a population-based case-control study involving 564 patients and more than 1100 normal healthy subjects. This study concluded that the subjects with Allium vegetable intake were at a significantly lower risk of developing stomach cancer compared with low intake. Similar epidemiological associations have been noted for esophageal cancer, prostate cancer,breast cancer, hepatic cancer, pancreatic cancer, and endometrial cancer.
Evidence for anticancer effects of garlic derives from both population-based case-control studies, and clinical and laboratory investigations using purified garlic constituents such as DATS. Mechanisms underlying cancer chemopreventive effects of DATS are not completely understood, but known pharmacological responses to this natural product include alteration in carcinogen-metabolizing enzymes, cell cycle arrest, induction of apoptotic cell death, suppression of oncogenic signal transduction pathways, and inhibition of neoangiogenesis.
(Molecular mechanisms of DATS-induced cell cycle arrest in human prostate cancer cells. The DATS treatment causes degradation of ferritin to cause an increase in levels of labile iron leading to ROS generation. The DATS-induced ROS generation results) .
Biochemical synthesis of DATS (CH2=CH-CH2-S-S-S-CH2-CH=CH2) begins with γ-glutamyl-S-alk(en)yl-L-cysteine, which is hydrolyzed and oxidized to produce alliin. Alliin is the odorless precursor of DATS. Processing of garlic (cutting or chewing) generates a vacuolar enzyme (allinase), which acts upon alliin to give rise to allicin and other alkyl alkane-thiosulfinates. Allicin and related thiosulfinates are decomposed to yield various sulfur compounds including DATS. It has been estimated that one gram of fresh garlic may contain 900-1100 μg of DATS.
(Molecular mechanisms and targets of cancer chemoprevention by garlic-derived bioactive compound diallyl trisulfide.
2011)
SKIN CANCER (Molecular mechanisms of garlic-derived allyl sulfides in the inhibition of skin cancer progression.2012 )
Another study demonstred the chemopreventive skin cancer effect and the mechanism of allyl sulfides in a chemical carcinogen-induced mouse skin cancer and cell line mode. The DATS treatment increases the ROS level and inflicts DNA damage and induces G2/M arrest, endoplasmic reticulum (ER) stress, and mitochondria-mediated apoptosis, including the caspase-dependent and -independent pathways. .
HEPATOCARCINOMA (Protective effects of garlic oil on hepatocarcinoma induced by N-nitrosodiethylamine in rats. 2012 )
Another study investigates the protective effects and the possible mechanisms of garlic oil (GO, diallyl trisulfide (DATS), and other allyl polysulfides are the most abundant compounds in garlic oil ) against N-nitrosodiethylamine (NDEA)-induced hepatocarcinoma in rats. Lipid peroxidation (LPO), antioxidant defense system, and apoptosis-related proteins were measured to investigate potential mechanisms.
For the purpose of preventing cellular damage induced by ROS, the organism has a lot of antioxidative defense system, including the non-enzymatic (mainly GSH) and enzymatic antioxidant defenses (including SOD, GST, GR, CAT and GPx). GSH plays an important role in maintaining the normal reduced state of cells and counteracting the harmful effects of oxidative stress. GSH can effectively scavenge free radicals and other oxygen species through nonenzymatic and enzymatic process by conjugation with GPx and GST . GPx ubiquitously exists both in cytosol and mitochondria of the hepatocytes. GST locates in cytosol and plays an important role in detoxification and excretion of xenobiotics. GST catalyzes the conjugation of the thiol functional groups of GSH to electrophilic xenobiotics, leading to elimination or conversion of xenobiotic-GSH conjugate . In such reaction, the GSH is oxidized into GSSG, which can be reduced to GSH by GR with the consumption of NADPH . In addition, GSH can also react with various electrophiles, physiological metabolites and xenobiotics to form mercapturates, which are catalyzed by glutathione S-transferase (GST). In addition to GSH and GSH-related antioxidant enzymes, other antioxidant enzymes including SOD and CAT also take important role in the antioxidant defense system. SOD can catalyze the dismutation of two superoxide radicals to H2O2 and O2.
This study demonstrated that GO counteracted NDEA-induced oxidative stress in rats illustrated by the restoration of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) levels, and the reduction of the malondialdehyde (MDA) levels in liver. Furthermore, the mRNA and protein levels of Bcl-2, Bcl-xl, and β-arrestin-2 were significantly decreased whereas those of Bax and caspase-3 were significantly increased.
(Effect of GO and NDEA on the protein level of Bcl-2, Bcl-XL, Bax and Caspase-3)
BREAST CANCER (Diallyl disulfide-induced apoptosis in a breast-cancer cell line (MCF-7) may be caused by inhibition of histone deacetylation. 2012)
Another research has focused on the use of fresh garlic to prevent or treat breast cancer . A study investigated the effect of various dietary products on morphological differentiation of the breast cancer cell line MCF7 and found that 2-3 hours of exposure to garlic extract (fresh but not boiled) was sufficient to arrest the growth and alter the morphology of MCF7 cells. The study demonstred that reduced levels of cyclin D1 and decreased phosphorylation of ERK1 triggered the morphological differentiation followed by the altered expression of E-cadherin, β-catenin, and keratin 8/18. Altered expression of p21, retinoblastoma (Rb), heat shock protein 27 (hsp27), and Src-associated in mitosis, 68 kDa (sam68) may have also contributed to the sustained growth reduction. DATS (diallyl trisulfide) showed the most potent anti-proliferative effects in human breast cancer MCF-7 cells .MCF-7 cells treated with DATS underwent apoptotic death and also exhibited increased DNA binding activity of AP-1. Which was blocked NAC and the JNK inhibitor. DATS induced phosphorylation of the antiapoptotic Bcl-2 and proteolytic cleavage of poly(ADP-ribose)polymerase (PARP) in MCF-7 cells. DATS treatment activated c-Jun N-terminal kinase (JNK).
Conclusions
Many constituents of garlic reportedly inhibited the growth and induced apoptosis of several types of cancer cells. Moreover, garlic derivatives require longer exposures to obtain growth inhibition. Research has revealed that DATS targets multiple pathways to inhibit cancer development, including potentiation of carcinogen detoxification, cell cycle arrest, induction of apoptosis, suppression of oncogenic signaling, and inhibition of angiogenesis. Because DATS exhibits other pharmacological effects, such as cardiovascular and anti-microbial effects, this compound can be classified as a promiscuous agent. This property is not unique to DATS because many other promising dietary cancer chemopreventive agents (e.g., cruciferous vegetable constituent sulforaphane) function similarly. However, promiscuity may be an advantage for cancer chemopreventive agents because pathogenesis of cancer is complex involving abnormalities in multiple checkpoints and signaling pathways.
