A Real Breakthrough in Our Understanding of Cancer!

The Science Behind Tumexal™

One of the most remarkable discoveries of the past decade has been that a very high percentage of all cancers, whether in humans or animals, have inactivating mutations in the p53 tumor suppressor gene. Clearly, eliminating p53 tumor suppressor protein activity is an important, even critical initiation event in the pathway to cancer. The p53 Tumor Suppressor protein is called “the guardian of the genome.” Why? The answer to that question has many parts. First, our world is not a safe place for our DNA, or those of our canine family members. DNA is constantly under attack from a variety of chemicals, some of which enter from the environment— including chemicals in the food we and our dogs eat— and some of which are part of the internal chemistry of life. But the point is that our DNA is under assault at every moment. This damage must be repaired before the cell enters the DNA synthesis phase of the cell cycle. If it isn’t, then that damage may become a mutation— a permanent change to the DNA sequence. Most mutations fall in harmless areas of the genome. But some alter the sequence of DNA coding for a protein, and some of these alterations occur in critical sites of critical proteins. These are so-called “driver mutations” that can transform a cell into a malignant caricature of what it is supposed to be.

The p53 tumor suppressor orchestrates DNA repair, like a conductor directing an orchestra. If there is a critical level of DNA damage in a cell, p53 will arrest the cell cycle at what is called the G1 check point. During this G1 arrest, p53 directs the activity of an array of DNA repair enzymes which remove the damaged bases and thereby prevent mutation. If the level of DNA damage is too great, p53 directs that the cell undergo a sort of programmed cell death, called apoptosis. When apoptosis occurs in a normal cell at the end of its life cycle, it is called senescence. When apoptosis fails to occur, for example if an inactivating mutation occurs in p53 itself, blocking its tumor suppressor function, cancer results. One of the most important discoveries made in the last decade has been that the majority of cancers are initiated by inactivating mutations in the p53 tumor suppressor gene. Just as an orchestra missing its conductor would create not a symphony but rather a cacophony, when p53’s tumor suppressor activity is missing, the affected cell skips G1 arrest and DNA is replicated before it can be repaired. This leads to a wildly enhanced mutation rate in cancer cells, creating an extremely heterogeneous tumor cell population. It is this heterogeneity— mutations that confer altered activity to virtually every gene in the genome in at least some cells of the tumor cell population— that makes cancer so difficult to treat. Somewhere in a large tumor cell population there is bound to be a mutation that confers resistance to virtually any drug on the planet. This is the reason that a cure for cancer continues to be so elusive. In virtually every case of cancer, it is not one cancer that must be treated but hundreds of thousands, even millions— because every cell in the tumor cell population is different and offers an individual opportunity to create a resistant clone to a particular drug.

P53 also plays a critical role in differentiation, the process by which each of the more than 200 different cell types in the human and canine body matures into an adult cell capable of the functions required of it within the tissue system of which it is a part. When p53 is inactivated by mutation, the cancer cells which result fail to mature. They continue to divide the way immature cells do, and never become fully competent in the functions required of them to be an integrated part of their tissue type. They begin to express genes that are supposed to be expressed only by other tissue types (“leaky gene expression”), or at other times in development, particularly fetal genes (“oncofetal gene expression”). Some of these fetal genes confer the ability to invade nearby tissues, and to metastasize to distant sites.

How does p53 carry out its critical roles in the cell? P53 is a transcription factor which can bind to a stunning array of genes and switch them on or off. One of the enzymes regulated by p53 is Adenosine Monophosphate Kinase, AMPK. As a cellular energy sensor, AMPK can set in motion a series of events resulting in autophagy, a process related to apoptosis in which the cell starts cannibalizing itself. Since tumor suppressor genes activate autophagy, and oncogenes (cancer causing genes) mostly inhibit autophagy, it is generally believed that AMPK-mediated autophagy suppresses cancer. After sensing the presence of activated oncogenes and other cellular stressors, p53 can activate AMPK to set this antiproliferative/anticancer process of autophagy in motion. Thus, at least a portion of p53’s tumor suppressor activity comes from its activation of AMPK.

p53 also interacts directly with another very critical enzyme involved in metabolism– Glucose 6-Phosphate Dehydrogenase (G6PD). G6PD is the rate-limiting step of what is called the Pentose Phosphate Pathway (PPP). PPP is the major source of NADPH, a cofactor required for many critical synthetic reactions in cellular biochemistry. G6PD has been found to be overexpressed in a wide variety of different cancers, and p53 inhibits it directly, by preventing G6PD monomers from combining to form the active dimer. Mutant p53 proteins that have lost their tumor suppressor activity cannot inhibit G6PD. Further support for the critical function of G6PD in cancer comes from the additional observation that another major tumor suppressor protein, PTEN, also inhibits G6PD. All of this suggest that inhibition of G6PD is a major mechanism of the p53 tumor suppressor and at least one other major tumor suppressor. (References available upon request).

Thus, these two mechanisms of action of the p53 tumor suppressor protein– activation of AMPK and inhibition of G6PD– appear to play a major role in p53’s tumor suppressor activity. If the portion of p53 activity mediated by these mechanisms could be restored to a tumor cell population, it is reasonable to hypothesize that some or all of the cancer process might be inhibited.

After more than 20 years of research, the scientists a CanineCare.US have developed a natural supplement, Tumexal, that duplicates these two critical functions of the p53 tumor suppressor– the activation of AMPK, and the inhibition of G6PD. We are now in the process of investigating the effects of Tumexal on various canine cancers. If your dog has cancer and you would like to find out how he/she can participate in this research program, please call 610 489 8284.