Drs. James and Dorothy Morre of Purdue University, Indiana, have identified tNOX as a protein receptor that is vital to the growth and survival of all human tumor cells.
tNOX is a variant of a normal protein receptor known as NADH oxidase (constitutive NOX or CNOX). CNOX is present on all living cells in Nature where it performs two important functions.
(a) The first function relates to the assembly of proteins, particularly the proteins that make up the cytoskeleton of the cell. CNOX does this by repeatedly breaking and then reforming proteins at their disulphide (-S-S-) bonds. This function is critical to cell enlargement, which must occur when a cell divides. After a cell divides, the two new daughter cells have a finite time in which to reach their normal size, otherwise they will self-destruct (apoptosis).
(b) The second function relates to the shuttling of electrons, particularly hydrogen, from inside the cell to the outside. This function also is thought to be linked to the facilitation of cell enlargement.
CNOX fluctuates between these two functions with a sequence that is repeated on a 24-minute cycle. It has been proposed that this cycle length is the basis of the circadian rhythm of every cell in Nature.
CNOX is a receptor that responds to growth hormones and growth factors.
tNOX is a variant of CNOX. Like CNOX, tNOX performs the same two biochemical functions, but with two important differences - (a) it operates on a shorter cycle of 22-minutes, and (b) it is unresponsive to growth regulating hormones and growth factors.
There is compelling evidence that the presence of tNOX is essential to the development of cancer. tNOX is present on all human cancer cells that have been tested to date. It is produced by a different gene to the one that produces CNOX, indicating that tNOX expression is normally suppressed in healthy cells.
Phenoxodiol specifically inhibits tNOX and has no effect on CNOX.
Exposure or cancer cells to phenoxodiol results in almost instantaneous inhibition of tNOX activity, and this is associated with immediate inhibition of cell enlargement. This specificity explains the restriction of the effect of phe oxodiol on cancer cells and the absence of any significant toxicity of the drug.
For more information on CNOX and tNOX, see 'Cell surface NADH Oxidases (ECTO-NOX Proteins) with Roles in Cancer, Cellular Time-Keeping, Growth, Aging and Neurodegenerative Diseases.' DJ Morre, DM Morre, Free Radical Research, 37, 795-808 (2003).
