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Silencing Cancers with Synthetic siRNAs

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

Article ID #91: Silencing Cancers with Synthetic siRNAs. Published on 12/9/2014

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http://pharmaceuticalinnovation.com/2012-12-09/larryhbern/Silencing Cancers with Synthetic siRNAs

The challenge of cancer drug development has been marker by less than a century of development of major insights into the know of biochemical pathways and the changes in those pathways in a dramatic shift in enrgy utilization and organ development, and the changes in those pathways with the development of malignant neoplasia.  The first notable change is the Warburg Effect (attributed to the 1860 obsevation by Pasteur that yeast cells use glycolysis under anaerobic conditions).  Warburg also referred to earlier work by Meyerhoff, in a ratio of CO2 release to O2 consumption, a Meyerhoff ratio.  Much more was elucidated after the discovery of the pyridine nucleotides, which gave understanding of glycolysis and lactate production with a key two enzyme separation at the forward LDH reaction and the back reentry to the TCA cycle.  But the TCA cycle could be used for oxidative energy utilization in the mitochondria by oxidative phosphorylation elucidated by Peter Mitchell, or it can alternatively be used for syntheses, like proteins and lipid membrane structures.

A brilliant student in Leloir’s laboratory in Brazil undertook a study of isoenzyme structure in 1971, at a time that I was working under Nathan O. Kaplan on the mechanism of inhibition of mitochondrial malate dehydrogenase. In his descripton, taking into account the effect of substrates upon protein stability (FEBS) could be, in a prebiotic system, the form required in order to select protein and RNA in parallel or in tandem in a way that generates the genetic code (3 bases for one amino acid). Later, other proteins like reverse transcriptase, could transcribe it into the more stable DNA. Leloir had just finished ( a few years before 1971 but, not published by these days yet) a somehow similar reasoning about metabolic regions rich in A or in C or .. G or T.  He later spent time in London to study the early events in the transition of growing cells linked to ion fluxes, which he was attracted to by the idea that life is so strongly associated with the K (potassium) and Na (sodium) asymmetry.   Moreover, he notes that while DNA is the same no matter the cell is dead or alive,  and therefore,  it is a huge mistake to call DNA the molecule of life. In all life forms, you will find K reach inside and Na rich outside its membrane. On his return to Brazil, he accepted a request to collaborate with the Surgery department in energetic metabolism of tissues submitted to ischemia and reperfusion. This led me back to Pasteur and Warburg effects and like in Leloir´s time, he worked with a dimorphic yeast/mold that was considered a morphogenetic presentation of the Pasteur Effect.  His findings were as follows. In absence of glucose, a condition that prevents the yeast like cell morphology, which led to the study of an enzyme “half reaction”. The reaction that on the half, “seen in our experimental conditions did not followed classical thermodynamics” (According to Collowick & Kaplan (of your personal knowledge) vol. I See Utter and Kurahashi in it). This somehow contributed to a way of seeing biochemistry with modesty. The second and more strongly related to the Pasteur Effect was the use an entirely designed and produced in our Medical School Coulometer spirometer that measures oxygen consumption in a condition of constant oxygen supply. At variance with Warburg apparatus and Clark´s electrode, this oxymeters uses decrease in partial oxygen pressure and decrease electrical signal of oxygen polarography to measure it (Leite, J.V.P. Research in Physiol. Kao, Koissumi, Vassali eds Aulo Gaggi Bologna, 673-80-1971). “With this, I was able to measure the same mycelium in low and high “cell density” inside the same culture media. The result shows, high density one stops mitochondrial function while low density continues to consume oxygen (the internal increase or decrease in glycogen levels shows which one does or does not do it). Translation for today: The same genome in the same chemical environment behave differently mostly likely by its interaction differences. This previous experience fits well with what  I have to read by that time of my work with surgeons.  Submitted to total ischemia tissues mitochondrial function is stopped when they already have enough oxyhemoglobin (1) Epstein, Balaban and Ross Am J Physiol.243, F356-63 (1982) 2) Bashford , C. L, Biological membranes a practical approach Oxford Was. P 219-239 (1987).”

Of course, the world of medical and pharmaceutical engagement with this problem, though changed in focus, has benefitted hugely from “The Human Genome Project”, and the events since the millenium, because of technology advances in instrumental analysis, and in bioinformatics and computational biology.  This has lead to recent advances in regenerative biology with stem cell “models”, to advances in resorbable matrices, and so on.  We proceed to an interesting work that applies synthetic work with nucleic acid signaling to pharmacotherapy of cancer.

Synthetic RNAs Designed to Fight Cancer