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EPIGENETICS, RONS & p53 and INTERFERON

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Epigenetics: turning on unwanted pathways in cancer 



Epigenetics is the study of changes in genes and gene activity in the absence of modifications of the DNA sequence. The enzymes involved in epigenetic processes ‘edit’ the DNA script, changing its interpretation. 

DNA is less a literal template than a blueprint or a framework on which to hang the drama of life, akin to a movie script, that is open to interpretation and by its very nature unrealizable except through translation by a director, who interprets the text. The process of ‘realizing’ the DNA blueprint involves literal edits, analogous to a director marking up a script with a pen. A crossed out line here, a transposed word, or an underlined sentence there and voila the emphasis of certain scenes in a script are completely changed. It’s the difference between the signature catchphrase from the 1939 film Gone With the Wind “Frankly, my dear, I don’t give a damn” uttered so dismissively and derisively by Rhett Butler (Clark Gable) and the more humdrum, laissez-faire “Frankly, my dear, I’m not sure I really care anymore” which delivers the same meaning, in a sense, but radically changes the emphasis and the impact. 

In the cell, these editorial modifications are referred to as epigenetic (“epi” meaning “above” or “in addition to”). In lieu of ‘pen marks’, enzymes called methyltransferases (MTases) and histone deacetylases (HDACs) add small chemical squiggles, methyl and acetyl groups, respectively, to DNA that change, not the underlying genetic sequence, but the expression and the interpretation of certain genes. In cancer, hyperactivity of the enzymes lead to repression or inactivation of important genes such as p53. Many genes that are silent in normal tissue become activated leading to cell transformation, proliferation and invasion, characteristics of the tumor phenotype.

p53: The universal cellular guardian angel 



The tumor suppressor, p53, acts as a primary response to cellular stress leading to a multitude of responses that depend on the type of the cell under stress, its transformational status and other factors that include the immediate surroundings such as hypoxia or oxidative stress. p53 not only defends the genome, but also guards against epigenetic changes, preventing cellular transformation and carcinogenesis. It is therefore not surprising that mutations in p53 that inactivate the defensive mechanism are common in many cancers and are associated with aggressive phenotypes.

RONS, epigenetics and p53 

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Increased production of reactive oxygen and nitrogen species changes the catalytic activity of the enzymes involved in epigenetic processes. In particular studies on the inhibition of HDACs or MTases have shown the potential of de-repression of p53 leading to reactivation of the “guardian angel” resulting in an innate tumor suppressive effect. Direct inhibition of these enzymes by new drugs or indirectly through RONS activity is therefore an exciting avenue for anticancer research.

Interferon

Emerging research places epigenetic inhibitors like RRx-001 at the intersection between epigenetics and anti-tumor immunity through the activation of a class of proteins called interferons, a type of cytokine, which stimulates the immune system to kill cancer cells. (See abstract of article by Chiappinelli et al about epigenetic inhibitors and interferon response)

Immunogenic Cell Death

RRx-001 and the VIMMUNE oncolytic viruses appear to induce immune dependent tumor cell death or immunogenic cell death (ICD). Therefore the immunomodulatory potential of these two cancer specific therapies represent an opportunity to induce in vivo an “anti-cancer vaccine” effect by merging epigenetics and anti-tumor immunity within a single paradigm.

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