Entremed (ENMD)

[C_Peptide]

Blocking glycolysis is the least of Panzem's effects

It is unfortunate that this quote, "Blocking HIF1 activity interferes with the tumor's ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth," was chosen for the article. The truth is much more complicated. 2-methoxyestradiol partly reverses a major "switch" in how cells become dangerous. Energy production is the least of a cancer cell's problems. Reducing the energy available to them will not help patients. After all, cancer cells have already reduced their available energy by 93%.

It has been known since the 1920s that cancer cells all but turn off the method of energy production called oxidative phosphorylation (OxPhos) which occurs in the mitochondria, in favor of glycolysis which occurs in the cytosol. In the process the energy efficiency of the cell is reduced to about 7% of normal, because OxPhos makes about 15x as much energy per molecule of glucose. Mitochondrial enzymes are also key players in the process of programmed cell death, called "apoptosis," which is triggered when a cell recognized that it is "broken." This is part of a larger de-differentiation of the cell to a more primitive, proliferative, invasive phenotype. If 2-ME2 can cause the cell to switch back to something resembling the cell it came from, by blocking the oxygen-independent expression of HIF-1, it is likely that programmed cell death will be the result, and failing that, a far less malignant cell.

Upstream of HIF-1 is the PI3K/AKT pathway, which is also blocked by 2-methoxyestradiol, and which among other things increases HIF-1 expression, lengthens telomeres, and promotes angiogenesis. It is an upregulated pathway in practically all cancers. It is a very important target for anti-cancer therapy.

Refs:
http://www.ncbi.nlm.nih.gov/pubmed/17680560
http://www.imgenex.com/emarketing/Akt_Signaling1_fullsize.jpg

Best Regards,
C-Peptide

P.S. Despite the development of analogues and the pharmacokinetic fiasco that was EntreMed's management of oral Panzem, let's not lose sight of the fact that 2-ME2 is what our own bodies have used for countless generations to regulate angiogenesis and cell proliferation, at least in certain circumstances. This confers an enormous presumption of safety. But, as a practical matter, ever since the discovery of insulin the delivery of concentrated physiologic molecules in a therapeutic way has been problematic. Analogues are here to stay, but what we lose in the pursuit of convenient delivery is the confidence that untoward effects are not likely to be lurking around the corner.