Daniele Tota.
Everyone knows that Popeye eats spinach for making himself super strong, but it is surprising that these vegetables protect him against inflammatory problems, oxidative stress-related problems, cardiovascular problems, bone problems and cancers.
Several studies identified more than a dozen different flavonoid compound in spinach that function as anti-inflammatory and anti-cancer agents.
Isolation and characterization of structurally novel antimutagenic flavonoids from spinach (Spinacia oleracea), 2001.
Spinach is an excellent source of vitamin K, magnesium, manganese, and calcium, folate, potassium, and vitamin B6, iron and vitamin B2 and free radical-scavenging vitamin A (through its concentration of beta-carotene), vitamin C and vitamin E. It is a very good source of fiber, phosphorus and vitamin B1 and the antioxidants copper and zinc.
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Vegetables are more important in our diet because of their important effects, including an anti-cancer effect. The anticancer properties of spinach have been sufficiently impressive to prompt researchers to create specialized spinach extracts that could be used in controlled laboratory studies.
Multiple organisms are known to contain 14 types of DNA-polymerase (pol) with catalyze both DNA replication and repair. Pol inhibitors cold be used as anti-cancer chemotherapy agent, because they inhibit cells proliferation. For this reason more studies have found many new inhibitors like long-chain fatty acids, conjugated fatty acid, bile acids such as lithocholic acid, steroidal glycosides, sulfo-glycolipid, catechins, curcumin, vitamin D2 and D3.
Anti-Tumor Effects of the Glycolipids Fraction from Spinach which Inhibited DNA Polymerase Activity, 2007.
Glycoglycerolipids.
In higher plants (e.g. spinach, algae and cyanobacteria) thylakoid membrane (the site of the light-dependent reactions of photosynthesis) are particularly rich in glycoglycerolipids, including Monogalactosyl diacylglycerol (MGDG), Sulfoquinovosyl diacylglycerol (SQDG) and digalactosyl diacylglycerol (DGDG). These major glycoglycerolipids are contained in vegetables, fruits and grains. MGDG and SQDG inhibit replicative DNA polymerase activity, meanwhile DGDG did not influence all mammalian DNA polymerases.
Anti-cancer Effect of Spinach Glycoglycerolipids as Angiogenesis Inhibitors Based on the Selective Inhibition of DNA Polymerase Activity, 2011.
It is possible to purify a major glycolipid fraction from a green vegetables, such as spinach.
As shown in Table 2, spinach ( Spinacea oleracea L .) had the largest amount of SQDG and, compared with other vegetables, the highest content in MGDG. Spinach was also the strongest pol inhibitors in the tested vegetables.
Inhibitory effects of glycolipids fraction from spinach on mammalian DNA polymerase activity and human cancer cell proliferation, 2005.
Structure of main glycoglycerolipid from spinach.
Chemical structures of major glycoglycerolipids from spinach are shown in the figure (R1 to R6 are acyl chains). (A) monogalactosyl diacylglycerol (MGDG), (B) digalactosyl diacylglycerol (DGDG), (C ) sulfoquinovosyl diacylglycerol (SQDG).
MGDG is a non-nutrient compound contained in vegetables, grains and fruits. The chemical structure of MGDG comprises two acyloxy groups (R1 and R2) derived from fatty acid molecules. Spinach MGDG is rich in n-3 α-linolenic acid. The fatty acid composition influences the antitumor effect. MGDG is digested to monogalactosyl monoacylglycerol (MGMG) and monogalactosyl glycerol (MGG) by a digestive enzyme and enterobacteria, respectively, and MGG is not absorbed. MGMG was absorbed and re-synthesized or that undifferentiated MGDG entered the blood stream. MGDG is not completely degraded and possesses antitumor activity, since components of MGDG, galactose and glycerol, do not have an antitumor effect, and fatty acids have a weak antitumor effect.
Oral administration of monogalactosyl diacylglycerol from spinach inhibits colon tumor growth in mice, 2013.
SQDG consist of a sulfoquinovose, a glycerol and two fatty acids. The two difference between MGDG and SQDG are:
1. The presence of an acidic group (i.e., a –SO3H group) on the sugar
2. The stereochemical differences at C-1 and C-4; therefore, both this acid side and the stereochemistry may be required for inhibition of pols activity.
Anti-cancer Effect of Spinach Glycoglycerolipids as Angiogenesis Inhibitors Based on the Selective Inhibition of DNA Polymerase Activity, 2011.
Effect of each glycoglycerolipid from spinach on the activities of the DNA metabolic enzymes.
Pols are essential for DNA replication, repair and recombination, and subsequently for cell division, inhibition of these enzymes will lead to cell death, especially under proliferation conditions. Inhibitors of eukaryotic pols should be considered potential agents for cancer chemotherapy.
DNA pol catalyzes the addition of deoxyribonucleotides to the 3’-hydroxyl terminus of a primed double-stranded DNA molecule. The human genome encodes at least 15 DNA pols that conduct cellular DNA synthesis. Eukaryotic cells contain 3 replicative pols (α, δ and ε), 1 mitochondrial pol (γ), and at least 11 non-replicative pols: β, ζ, η, θ, ι, κ, λ, μ, ν, terminal deoxynucleotidyl transferase (TdT) and REV1. Pols have a highly conserved structure and their catalytic subunits showing little variance among species. On the basis of sequence homology, eukaryotic pols can be divided into four main families, termed A, B, X and Y. Family A includes mitochondrial pol γ as well as pols θ and ν. Family B includes the three replicative pols α, δ and ε and also pol ζ. Family X comprises pols β, λ and μ as well as TdT; and last, family Y includes pols η, ι and κ in addition to REV1.
MGDG selectively inhibited the activities of human pols γ, δ and ε. The inhibitory effect on B-family pols α, δ and ε was stronger than on A-family pols. On the other hand, MGDG did not influ-ence the activities of the X-family pols (pol β, pol λ and TdT), which are important for DNA repair and/or recombination. The inhibitory effect of SQDG in more than 10-fold stronger than that of MGDG.
SQDG and MGDG are potent mammalian pol inhibitors. Using poly(dA)/oligo(dT)18 and 2'-deoxythymidine 5'-triphosphate (dTTP) are used as the DNA template-primer and nucleotide substrate in was shown that:
- MGDG and SQDG inhibit pol α activity in a non-competitive way with respect to both the DNA template-primer and the NTP substrate.
- the inhibition of pol β by SQDG was competitive with both DNA template-primer and dNTP substrate.
The experiments show that MGDG and SQDG may interact with both of the binding sites on DNA polymerase β, decreasing its affinity for the DNA template and substrate. The manner of inhibition by fatty acids against pol α was non-competitive, indicating that the fatty acids bound to a site other than the catalytic site.
Structure and activity relationship of monogalactosyl diacylglycerols, which selectively inhibited in vitro mammalian replicative DNA polymerase activity and human cancer cell growth, 2009.
EFFECTS OF SPINACH GLYCOGLYCEROLIPIDS ON HUMAN CANCER AND NORMAL CELL GROWTH
A significant correlation has been found between MGDG content and the inhibition of replicative pols; therefore, MGDG penetrate cancer cells and reach the nucleus and mitochondria, thus inhibiting mammalian pols α, γ, δ and ε activities and leading to human cancer cell growth suppression. The mechanism of selective cell growth suppression between cancer and normal cell lines by MGDG remains unclear, and it may be considered that the expression amounts and activities of pols α, δ and ε, which are nuclear DNA replicative pols, as well as pol γ, which is a mitochondrial DNA replicative pol, in cancer cells are higher than in normal cells and, thus, MGDG could only inhibit cancer cell proliferation.
In vivo study using MGDG were relatively difficult to perform because of its solubility. To solve this problem, liposomes were prepared which had sialyl Lewis X (SLX) bound to their surfaces and containing spinach MGDG (SLX-Lipo-MGDG). Liposomes are used as a drug delivery system (DDS).
Several experiments demonstrated that MGDG suppressed the growth of all six human cancer cell lines tested, including A549, BALL-1, HeLa, HL60, HT-29 and NUGC-3.
In vivo antitumor effect of liposomes with sialyl Lewis X including monogalactosyl diacylglycerol, a replicative DNA polymerase inhibitor, from spinach, 2012.
After MGDG was found to selectively inhibit the activities of mammalian replicative pols and human cancer cell growth, the effect of this compound on cell cycle regulation was investigated.
Cyclin A and cyclin E proteins, which are regulated in G1/S-phase, increased with MGDG treatment, whereas cyclin B, which is regulated in G2/M-phase, decreased significantly. These results indicate that MGDG induces G1- and S-phase arrest in human cancer cells, suggesting that cancer cells treated with MGDG, which inhibits the activity of replicative pols, overcome the S-phase block, divide, enter a new G1-phase and then stop cycling, being unable to replicate DNA and pass the G1/S checkpoint.
MGDG from spinach causes cell cycle and the inhibition of mammalian replicative pol activity by this compound has a strong apoptotic effect on human cancer cells.
Anti-cancer effect of spinach glycoglycerolipids as angiogenesis inhibitors based on the selective inhibition of DNA polymerase activity., 2011.
INHIBITORY EFFECTS OF SPINACH GLYCOGLYCEROLIPIDS ON ANGIOGENESIS.
In vitro MGDG was found to completely inhibit HUVEC (human umbilical vein endothelial cells) tube formation in a dose-dependent way. On the other hand, SQDG showed a weak inhibitory effect. Overall, MGDG was the most effective glycoglycerolipid and SQDG shows no inhibitory effect on cell growth, although SQDG inhibited pols more potently than MGDG. It seems that MGDG can exert a suppressive effect on HUVEC proliferation by inhibiting mammalian replicative pols. However, pols are not direct targets in the HUVEC tube formation assay; therefore, MGDG might be able to affect signal transduction pathways in endothelial cells.
Anti-cancer effect of spinach glycoglycerolipids as angiogenesis inhibitors based on the selective inhibition of DNA polymerase activity., 2011.
ANTI-TUMOR ACTIVITY OF SPINACH MGDG, IN A MOUSE MODEL.
MGDG has shown to suppress the cell growth of mouse cancer cell lines, with almost the same cell growth inhibitory results as cancer cell lines from humans. Mice were treated with administration of oral MGDG. This induced suppression of colon tumor growth with inhibition of angiogenesis and the expression of cell proliferation markers as Ki-67 and Cyclin E.
Glycolipids, especially MGDG and SQDG, are hydrolyzed and yield monogalactosyl monoacylglycerol (MGMG) and sulfoquinovosyl monoacylglycerol (SQMG), respectively, and MGMG and SQMG increased the inhibition of DNA polymerase activity, anti-proliferation of cancer cells and tumor suppression more than MGDG and SQDG.
Anti-Tumor Effect of Orally Administered Spinach Glycolipid Fraction on Implanted Cancer Cells, Colon-26, in Mice, 2008.
CONCLUSIONS.
Spinach are not only important for Popeye. Thylakoid membranes in plant chloroplasts have a crucial role in possessing photosynthetic electron transport and photophosphorylation systems for the conversion of light to chemical energy. MGDG, DGDG and SQDG, are three glycoglycerolipids in the chloroplast membrane. MGDG and SQDG have anti-tumoral effect, including anti-proliferative, anti-angiogenesis and apoptosis-inducing activity; therefore they have cancer-preventing and health-promotion effects.
