Cancer stem cells (CSCs) are a highly aggressive type of malignant cell in terms of differentiation, self-renewal, resistance to tumor therapy, and metastatic capacity. They can remain after surgery, chemotherapy, radiotherapy and are the cause of relapses. Among the various theories of carcinogenesis, which I share the view that tissues are organized around real "social relationships" whose loss leads to the onset of manifestation after the change of the "microenvironment" for both changes in the genome o due to changes in monitoring mechanisms or due to changes in signal transduction within the cell.
Over the past 10 years, for no apparent reason, more than 150 therapies for the elimination of CSC have been attempted to destroy them using as targeting their surface antigens, CSC-bound oncoproteins, intracellular regulatory pathways and drug resistance pathways.
no anti-CSC drug has been put into clinical use and is shared by all KEPs after chemotherapy, is drug resistant, remains on standby for one year.
A few months ago he was released with Carcinogenesis, an experimental original work of 17 research teams from 14 Spanish and American centers, which shows in animals, a polyphenol (secoiridoide) dell'EVOO, [decarboxymethyl-eleuropein unsweetened (DOA) has inhibitory action in CSC, in both metabolic (mTOR) and epigenetic (DNMT) directions.
The study involved the CSC breast where they are present in two forms, reversible and interchangeable, one epithelial type, characterized by the expression of dehydrogenase aldehyde (ALDH +) and the other of the mesenchymal type, characterized dall'immunofenotipo CD + CD44, CD24 and ALDH are markers of CSC in the chest). Epitheliomesenchimale transition, caused by extracellular signals and growth factors, is a molecular reprogramming with new instructions for the cell and is essential, under normal conditions such as embryogenesis or organogenesis, while in pathological conditions (carcinogenesis), it is the cause the formation of fibroblast cells characterized by the ability to invade and migrate.
Plant evolution has created a rich source of refined and multi-rooted plant protection products to eliminate environmental pressures including protection against fungi, insects and predators. Among the polyphenols dell'EVOO the DOA comes dall'europeina lost, enzymatic, glucose (unsweetened? A = deprivation in the sense and Glicone = part of the sugar, bound helenic acid) has also lost the carboxylic group, esterified with methyl, (de = in the private sense in de-carboxymethyl-) previously associated with helenolic acid. Elenolic acid is attached to an ester bond, then hydrolysable, to hydroxytyrosol which, with two hydroxyl groups of the phenolic ring, represents the bioactive moiety of DOA. The phenolic ring of DOA binds to different amino acid residues (tryptophan, glycine, valine) of the enzymatically active site of mTOR that changes configuration and activity. The concentration of DOA in EVOO quality ranges from about 48 to 631 mg / kg (median value 185), I think it is useful to know, in addition to the quantitative dosage of total polyphenols, the phenolic profile.
MTOR (Rapamycin Small for Mammalian Target, the target of rapamycin in mammals) is an enzyme with protein-kinase activity (capable of phosphorylating a serine-threonine protein), phosphorylation activating cellular marker factors Akt / mTOR are involved in many cell functions (cell growth, angiogenesis, mitochondrial metabolism, lipogenesis, apoptosis and autophagy, protein synthesis, transcription, motility and cell proliferation, telomerase translational and meta-translational activity). It acts on more than 100 genes and proteins involved in the cellular response.
In many human tumors, hyperactivity of mTOR was detected, thus representing an important therapeutic target.
MTOR senses cellular nutrients (via AMPK α), chemical energy levels (AMP + ADP / ATP) and the redox state of the cell thus is a "general switch" of the anabolic and catabolic cellular processes associated to greater metabolic activity.
DOA inhibits the catalytic region of the mTOR protein kinase where ATP is bound to yield phosphorus molecules - rich in chemical energy - to molecules for activation downstream of P3K / Akt / mTOR. In practice, the inactivating effect of DOA kinase is similar to that of rampamycin.
Rapamycin [isolated in the 1970s in a soil sample for Rapa Nui (Easter Island) from the bacterium Streptomyces hygroscopicus] has antifungal, immunosuppressive and anticancer activity]; It is the first selective inhibitor of mTOR, but over the years, other P3K / Akt / mTOR inhibitors have been discovered that improve the biological response along with a more comprehensive antitumor activity.
The mode of the PIP signal is activated by nutrients (glucose, amino acids, ac. Fat), insulin, other hormones, growth factors, cytokines, mitogens, while the opposite is iporegolata reduced energy availability (as calorie restriction is provided) activation of AMPK (activated protein kinase AMP) and Sirtuins that reduce mTOR activation. Among the factors that inhibit the activity of mTOR, in addition to calorie restriction and rapamycin also metformin (used in the treatment of type 2 diabetes), some natural compounds, including resveratrol (grape skin), curcumin (curcumin) (curcumin) -catechin (tea), genistein (soy), indole-3-carbinol and sulforafani (broccoli, cabbage, Brussels sprouts, cauliflower),
a) maintains the function of stem cells in many tissues, improves remedial capacity and slows the progression of age-related diseases, prolongs survival;
b) inhibits the proliferation of divergent cells.
DNMT is the enzyme DNA methyltransferase capable of methylating nitrogenous bases of DNA by transferring methyl groups from the "donor molecule" S-adenyl-methionine (SAM): DNA methylation determines the silencing of genes without altering their expression (epigenetic) sequence.
Methylation of tumor suppressor genes promotes oncogenesis and metastasis.
In this case, DOA, which binds to the DNA-binding enzyme region, inhibits DNMT methylation activity to tumor suppressor genes rather increases the expression of the tumor suppressor of the metastatic phenotype undifferentiated including Spread 1-2 and SMURF2.
Aglycone eleuropein (OA), a precursor to DOA, inhibits CSC tumor transformation with reduced activity by 50% compared to DOA for which only the latter has been studied. In fact, of the 609 stem cell-related genes, DOA 160 will alter expression (Ex: Epigenetic inactivation of ALDH1A1, Oct4, TER telomerase; Activation and stimulation of metastatic repression genes suppressed as SPR21 -2 SMUR expression of WRN, FOS, c-ASP3 that promote stem cell differentiation). These effects of DOA occur in very low doses, micromolar, also the effect is dose-dependent from 1 to 20 micromoles / l.
Oleic acid also has anti-CSC activity, but has been shown to be half as effective as DOA.
Finally erase the epigenetic factors DOA that determine the stem cell of the CSC, while stimulating the genes that contribute to cell differentiation, epigenicamente suppressed, despite actually related programs programmed cell death (apoptosis).
In practice, DOA facilitates the maturation of cancer stem cells, losing their oncological character despite the fact that they have been determined to die.
bibliography
Corominas-Faja B. Et al. Extra virgin olive oil contains a metabolic epidermal inhibitor of cancer stem cells. Carcinogenesis. 2018? 39 (4): 601 - 13. DOI: 10.1093 / carcin / bgy023.
Dogan F. et al. Correlation between telomerase pathway and mTOR in cancer stem cells. Gene. 2018? 641: 235-39 DOI: 10.1016 / j.gene.2017.09.072
Schenone S. et. Competitors mTOR ATP antagonists: an update. Curr Med Chem. 2011? 18: 2995 to 3014. DOI: 10.2174 / 092986711796391651
by Alessandro Vujovic published on 28 September 2018 in Strettamente Tecnico> L'arca olearia Reblog http://www.teatronaturale.it/
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