Article continued…

An important piece of news: We have two types of mutation—to the p53 gene itself or to the protein itself. Even with a WT p53, mutated protein can be produced and considered as a post-translational event during protein modification. The mutated p53 gene is considered as a post-transcriptional mutation. p53 mutation (or p53 mutant protein) is associated with aggressive tumors increasing cancer cell resistance during chemotherapy but has also a prognostic and predictive value for poor response, metastasis invasion, and increased recurrence during chemotherapy regimens.

Some studies have found that the presence of mutated p53 (14 out of 19 cases) was associated with a poor response to various chemotherapy or radiotherapy regimens in breast, colorectal, ovarium, stomach, and soft tissue carcinomas. Sixty-five out of 93 studies found that mutant p53 (WT p53 increases cell death) is a statistically significant factor of poor prognosis in various cancers.

Texas researchers found, from a study of 1,500 breast cancer patients treated with mastectomy and chemotherapy, that high levels of p53 mutated protein accumulation are associated with a significant increase in local recurrence rate. There was about a 40% lifespan reduction in breast cancer patients at five-years survival, who harbored a p53 mutation, compared to patients with a  WT p53.¹⁹

p53 Inhibits the Warburg Effect by Reducing Glycolysis and Enhancing Oxidative Phosphorylation

Besides being a tumor suppressor gene associated with apoptosis, which I had previously presented in the Townsend Letter (August/September 2015), p53 has other important functions, although these are less known or even ignored. They have not been discussed before, so this is all new for our readers. You have to work with p53 in clinical applications and look behind its normal function as a tumor suppressor. I discovered that WT p53, but not the mutated p53 gene or protein, inhibits glycolysis. Therefore, this offers a new approach and way to treat cancer. Furthermore, these functions also provide another approach to one of the main hallmarks of cancer known as the Warburg effect.²⁰ This is accomplished by regulating glycolysis and shutting down glycolysis transporters as well as other expressions of the glycolysis enzyme promoting oxidative phosphorylation (oxphos) through transcriptional regulation of target genes. p53 can inhibit glycolysis; but when mutated or misfolded, p53 stimulates glycolysis that cancer cells use to generate energy and contributes to cancer progression. Thus, by p53 balancing the use of glycolysis and oxphos, it provides a mechanism blocking tumorigenesis and the Warburg effect.

Glycolysis is the pathway that tumors use as an alternative for generating energy via oxidative phosphorylation or respiration in mitochondria to generate so-called ATP molecules from sugar burned or oxidized in the presence of oxygen and broken down into C02 and H20.

Oxygen reduction in the mitochondria and blockage of the cellular respiratory chain from deficient respiratory enzyme and other electron chain transport damage (or mtDNA mutation observed in a variety of human cancers) may further contribute to respiratory malfunction in cancer cells. The German biochemist Otto Warburg proposed in 1924 that cancer was caused by a defect of oxphos or respiration in the mitochondria forcing cells to switch to the old primitive glycolysis channel when oxygen cannot be used by the mitochondria to generate cellular ATP energy.^21-23

Otto Warburg, who was the director of the famous Max Planck Institute for Cell Physiology in Berlin, won his first Nobel Prize for physiology and medicine in 1931 for the oxygen transfer enzyme of cell respiration. His second Nobel Prize in 1944 was for his discovery of hydrogen transferring enzymes. This latter process does not require oxygen because it arose early in the primordial evolution of prokaryotic cells back when the earth’s atmosphere had very little oxygen. Warburg analyzed the ratio of oxphos to glycolysis in different cancer cell tissues and found that glycolysis under anaerobic fermentation was particularly high in aggressive tumors when compared with benign tumors and normal tissues. These observations led Warburg to propose a deficiency in oxphos and elevated glycolysis as the primary cause of cancer. Today the Warburg effect is now enjoying a resurrection and has started to be taken very seriously by several researchers and even doctors and oncologists. 

Phosphorylation and Aerobic Respiration in Mitochondria

The glycolytic pathway is found in the cytoplasm of each cell that does not require oxygen. However, glycolysis pathways produce ATP less efficiently than aerobic respiration, resulting in the production of only two molecules of ATP per molecule of glucose while 36 molecules of ATP are produced in oxphos; yet cancer cells possess a 20- to 30-fold increased rate of glucose cellular uptake and a more than 30-fold higher glycolytic rate when compared to normal cells. Cancer cells produce ATP from glycolysis a hundred times faster than normal cells²⁴ in order to support three basic needs of these cells: 1) Maintenance of energy status, 2) Increased biosynthesis of macromolecules such as proteins 3) Maintenance of the cellular redox status, which permits survival and growth. Several studies have already shown that WT p53 plays a crucial role in slowing down or inhibiting glycolysis and at the same time promotes oxphos and cellular respiration through transcriptional regulation of target genes. Mutant protein or even misfolded protein, which has lost its anti-tumor capabilities, triggers glycolysis to favor cancer progression.²⁵ p53 is mutated in many tumors and thus can influence aspects of both glycolysis and oxphos, thus being significantly important in contributing to the Warburg effect.

How Cancer Cells Use Glucose

Cancer cells use glucose to generate energy; its entrance into the cells from the increase of the glucose receptors on the surface is deferentially mediated by glucose transporters and then converted in pyruvate, which is then further converted in lactate.

Cells with high rates of glycolysis produce more lactate and exhibit decreased mitochondrial respiration compared to cells with WT p53, indicating that WT p53 suppresses aerobic glycolysis. The family of transporters that mediate the transport of glucose is comprised of four major transporters including GLUT1, GLUT2, GLUT3, and GLUT4. Each of the GLUT transport proteins possesses different affinities for glucose and other hexoses such as fructose. GLUT1, GLUT2, GLUT3,  and GLUT4 have a high affinity for glucose, allowing transport of glucose at a high rate under a normal physiological process^26-28 but also by the tumor cell. Tumor cells badly need glucose, thus increasing cellular intake associated with increased and deregulated GLUT transport expression. In fact, glucose uptake mediated by GLUT1 appears to be critical in the early stages of breast cancer development, affecting cell transformation and tumor formation.²⁹ But other glucose transporters such as GLUT2, GLUT3, and GLUT4 are also expressed in breast cancer and other cancers,^30,31 correlating with a poor prognosis.³² GLUT1 and GLUT3 are associated with cancer cell resistance to radiotherapy or chemotherapy.³³

Another example of p53 directly repressing the transcriptional activity of GLUT3 gene expression is shown by the indirect repression of IKK kinase complex, a central regulator of NF-κβ activation. As already described, WT p53 can reduce intracellular uptake of glucose by downregulating the glucose transporters by directly repressing gene coding resistance for the glucose transporter^34.35; in contrast, mutated p53 gene expression stimulates glycolysis, which is an additional oncogenic function of the mutated gene.

However, WT p53 can use other channels to regulate glycolysis by promoting Tigar (Tp53-induced glycolysis and apoptosis regulator) gene expression and by down-regulation of PGM (phosphoglycerate mutase). Tigar is gene-regulated as part of the p53 tumor suppressor pathway,³⁶ which encodes a protein similar to glycolytic enzymes. This recently discovered enzyme primarily functions as a regulator of glucose in human cells. This protein functions by blocking glycolysis and also protects cells from DNA damaging reactive oxygen species, further providing some protection from DNA-damage-induced apoptosis. PGM is a polypeptide derivative that can inhibit glycolytic flux. WT p53 down-regulates PGM, but mutated p53 enhances PGM activity, thus increasing glycolysis flux. Therefore, the downregulation of PGM expression and activity by WT p53 can inhibit the glycolysis pathway.³⁷

p53 Promotes Oxidative Phosphorylation

One of the important but probably lesser known functions of p53 is the regulation of the metabolic versatility of cells by favoring mitochondrial respiration over glycolysis, oxidative phosphorylation (oxphos), and reversal of the Warburg effect. In mitochondria (MT), the key components involved in oxphos and MT respiration are cytochrome C oxidase synthesis (critical for regulating oxygen utilization by the cell) and cytochrome C oxidase (COX), which can be directly trans-activated by WT p53. Cytochrome oxidase or Complex IV is encoded in humans by the SC02 assembly factors (synthesis of cytochrome oxidase) and critical to catalyzing the transfer of electrons from cytochrome C into molecular oxygen necessary for aerobic ATP production.

SCO2 is required for the assembly of the MT DNA encoded cytochrome C oxidase (COX IV) sub-unit into the COX complex found in the mitochondria electron transport chain, serving as the site of mitochondrial oxphos in mammalian cells. Loss of p53 supports a switch from aerobic respiration to glycolysis through the disruption of COX IV function, which decreases cellular dependence on oxygen. Therefore, SCO2 disruption with mutant p53 in human cancer cells aggravates the metabolic switch into glycolysis. Activation of WT p53 could increase SCO2 expression and thereby stimulate MT respiration and ATP production.^38,39 Studies have shown that WT p53 can directly upregulate the COX I gene encoding sub-unit of the COX complex found in colon cancer cells. This may contribute to the maintenance of MT cytochrome C oxidase and Complex IV in the electron transport chain.

p53 can also transcriptionally activate the apoptosis-inducing factor (AIF), a protein that maintains the integrity of Complex I in the MT electron transport chain. One other key function of AIF is to initiate the caspases-independent apoptosis pathway after the release of cytochrome C by the mitochondria. Thus, WT p53 plays an important role in enhancing MT oxphos in cancer cells, reactivating oxphos, and shutting down glycolysis, all being considered as a potential cancer therapy.

Telomerase Activity and p53 Tumor Suppressor Gene in Cancer

A growing number of studies are now showing the implication of telomerase overexpression in the malignant transformation and progression of the human tumor.⁴⁰ Telomerase is a large ribonucleoprotein complex in nature, a reverse transcriptase enzyme that carries RNA molecules used as a template to elongate telomeres. The molecules consist minimally and essentially of the protein catalytic subunit coded for human telomerase reverse transcriptase (hTERT) and telomerase associated protein (hTEP1). Its role is to maintain telomere integrity in the sequences of the eukaryotic chromosome ends. This prevents the ends from undergoing DNA damage response, playing a critical role in chromosome replication. This telomerase activity regulates dividing cells maintaining the telomere ends against erosion of their normal length.

As we age, have excess oxidative stress, or are exposed to radiation, telomeres gradually shorten. This shortening leads to cell aging, cell death, or senescence. Some somatic cells lack sufficiently high levels of telomerase to maintain their telomere length for an indefinite number of divisions. Consequently, these telomeres gradually shorten as cells age. This is why telomere activity has been widely studied as an aging factor.⁴¹

While normal somatic cells show varying telomerase activity, cancer cells express abundantly high telomerase. This may be considered a relevant factor to distinguish cancer cells from normal cells. It’s as if cancer cells use telomerase to divide indefinitely. Telomerase up-regulation/reactivation has been observed in 85% of all human tumors. Such tumors may become immortal and play a crucial role during human tumor pathogenesis.⁴² Besides being found in primary tumors, telomerase activity is also detected in circulating tumor cells, for example in breast,⁴³ ovarian,⁴⁴ and prostate cancers.⁴⁵

Many cancer cells are considered immortal because telomerase activity allows them to divide virtually forever because they possess the ability to continually regenerate their telomeres.⁴⁶ With telomere activation, some types of cells and their offspring become immortal because they bypass the Hayflick limit, thus avoiding all death as long as the conditions for their duplication are met. Many cancer cells are considered immortal because as mentioned telomere activity allows them to live much longer than any other somatic cells. A good example of immortal cancer cells is HeLa cells, which have been used in laboratories as model cell lines since 1951.

These cancer cells become resistant; and under several circumstances, they acquire some stem cell characteristics known as a cancer stem cell-like state (CSCs). They need to adapt to an ever-changing environment in order to survive. This is accomplished through genetic changes such as oncogene activation, tumor suppressor gene inactivation, epigenetic changes such as hypomethylation/hypermethylation, and metabolic changes with a shift to anaerobic glycolysis. These resistant cancer cells develop a very strong DNA repair mechanism, more rapidly than normal cells. While chemotherapy can damage them, they can repair quickly.

The p53 tumor suppressor gene, independently of inducing cell cycle arrest and apoptosis, seems to also play a crucial role in protecting telomeres from DNA damage by regulating telomerase activity through a crosstalk node employing two important mechanisms.⁴⁷ According to a recent discovery led by Paul Lieberman of the Wistar Institute, this is a particularly new function of p53 that had never been described previously. Both telomeres and p53 play an important role in the maintenance of genome integrity and tumor suppression They easily could be regarded as guardians of the genome.⁴⁸ The local binding of p53 to the region close to the amino terminus of telomerase associated protein 1 (hTEP1) is one response to DNA damage, protecting the telomere. Wild type p53 further represses telomerase enzymatic activity through downregulation of its protein catalytic subunit, human telomerase reverse transcriptase (hTERT) together with the interaction of the specificity protein 1 (transcription factor Sp1). Wild type p53 protein level prevents telomerase from becoming overactive and proliferating indefinitely. p53 mutation and accumulation of mutant protein correlate with telomerase over-activity in many cancers, such as ovarian cancer,⁴⁸ breast cancer,^49,50 and non-small cell lung cancer (NSCLC).⁵¹ I have also personally observed this during the past few years with other cancers in patients with bladder cancer, sarcoma, and prostate cancer.

With the activation of telomerase, some types of cells and their offspring possess the ability to continually regenerate their telomeres, by dividing continuously. This increases their lifespan and immortality. On the contrary, telomerase shortening provides a barrier to cancer progression where the majority of cancer cells depend on telomerase activation to gain proliferative immortality. If the p53 gene is more activated than telomerase, cancer cells, in all probability, are not yet immortal. They have a limited lifespan and can be destroyed. If telomerase is more highly activated than the p53 gene, cancer cells are out of control and become immortal. p53 gene expression leads to more effective control over the telomerase activity and prevents cancer cells from becoming immortal cells.

Telomerase upregulation/reactivation is observed in 85% of all cancers—and up to 90% in breast cancer—suggesting a crucial role during human tumor pathogenesis. The p53 tumor suppressor gene is mutated in 50% of all cancers. Both p53 mutation and overexpressed telomerase are considered an important event in earlier cancer development and disease progression with metastasis invasion. Over-expression of WT p53 was shown to down-regulate the telomerase enzymatic activity.

The role of the p53 tumor suppressor gene is to kill cancer cells via apoptosis and prevent them from continuously dividing, thus preventing cancer cells from reaching a more aggressive stem-like state.

Mutant p53 and overactive telomerase allow cancer cells within a tumor to turn back time by acquiring a stem-cell-like state (CSCs) by developing survival factors. This type of aggressive cell usually emerges during the later stage of tumor development facilitated by the loss of p53. They possess the ability to self-renew, differentiate by forming resistant phenotypes, and produce metastasis activity, chemo-resistance,^52,53 failure of treatment, and tumor relapse. These CSCs display high levels of telomerase activity possessing the ability to continually regenerate their telomeres.⁵⁴ The WT p53 tumor suppressor gene, indeed, plays a more crucial role than we may have initially learned, such as inducing apoptosis. When activated with the production of normal protein, it prevents established cancer cells from moving toward a more aggressive stem-like state, especially by regulating telomerase activity.

If the tumor suppressor gene is malfunctioning due to a lack of protein production or mutated protein, telomerase can become overactive. This means that along with the transformation of cells by mutated p53 into cancer cells, there is a high probability they also may be able to form a tumor. Fortunately, we can evaluate the presence of cancer cells capable of forming a tumor in the case of a non-cancer (diagnosed) patient, meaning we start at a preventive level. It is important to evaluate the activity of these two genes with the telomerase/p53 ratio for cancer patients under treatment or, even better, before starting treatment.

We have to know if the p53 gene is more activated than the telomerase or vice versa to determine the presence of non-resistant CSCs or, in a case of cancer remission, if there remains a presence of cancer cells somewhere in the body with a high risk of recurrence.

On several occasions, I have seen as a result of testing cancer patients in remission a bad p53/telomerase ratio. This includes the presence of mutated p53 protein. We already know by experience that cancer recurrence is still high in such breast cancers. We have not come across any other technique that permits clinicians to evaluate recurrence risk.  p53 mutation by itself together with BcL2 overexpression represents a sign of high-risk for cancer recurrence as I have often observed in several breast cancer patients. New studies have shown that telomerase reverse transcriptase (TERT) overexpression upregulated the expression of BcL2 and downregulated Bax activity reducing the activation of some caspases proteins such as caspase 9.^55,56 This explains why sometimes, even if p53 is highly expressed, BcL2 expression is also high even if normally activated; BcL2 can be overexpressed because of overexpression of TERT in the telomerase. There is a feedback mechanism between the two that we will develop further in my blog. Thus, a bad p53/telomerase ratio suggests the presence of CSCs with resistance to apoptosis and chemotherapy. Remember that overactive telomerase provides immortality to cancer cells if not regulated by WT p53 and the production of normal protein.

Telomerase activity may be seen as a new marker for cancer. In fact, the levels of telomerase activity (independent of the p53 gene) in the early and late stages of cancer might be used to determine the diagnosis of various human cancers as well as a biomarker for detection.

Ratio: p53/Telomerase Activity – A New Way to Diagnose Cancer

For nearly 15 years I spent considerable time studying and researching molecular markers, especially the p53 gene. I also studied a variety of selected natural compounds that exhibit anti-tumor activity targeting most of the mechanisms used by the tumor to grow and expand. One of the most important biomarkers used with p53 was the telomerase enzyme. An important strategy is to reactivate (restore) mutated p53 to a normal function, such as normal p53 protein production level, together with downregulation of telomerase activity and decreasing glycolysis. For this purpose, we can just perform a blood test with molecular markers. We include p53 gene expression, p53 protein level, BcL2, Bax, survivin, P21 gene expression and proteins, VEGF, MMPs, TNFa, and telomerase activity. As previously explained, telomerase upregulation is observed in 85%-95% of all cancers; and p53 is mutated in more than 50% of all cancers. If not mutated, p53 is often poorly activated. Activated WT p53 downregulates telomerase enzyme activity; therefore. if we have the difference from the activity of a WT p53 gene and the activity of telomerase—or differently from a failure or mutated p53 gene and the high expression of telomerase—surely we can determine a ratio, just as we do for Bax/BcL2.

I believe—first from my study of a number of scientific articles and secondly from my personal clinical experience—that targeting p53/telomerase activity remains today a major challenge in oncology. Theoretically, science has been researching synthesized compounds or drugs that can inhibit telomerase, same as with the reactivation of mutant p53. In the meantime, we already have on hand a range of natural compounds that have demonstrated efficacy to inhibit telomerase activity with no side effects. I am going to explain further.

In order to offer such services, we work with a laboratory specializing in biological assays that is directed by Dr. Olga Galkina Taylor, PhD, a highly reputed Russian scientist who opened a new door in my professional life. I have collaborated with Dr. Galkina’s laboratory for over 15 years. We have started working on the p53/telomerase ratio, which she developed; but so far, her work has never been published. In this article, I am presenting for the first time a preliminary introduction with some examples of clinical cases. We conjointly wrote an article in the Townsend Letter in August/September 2010 explaining how to reverse p53 mutation with my own therapy protocol,⁵⁷ but it probably came out too soon to be well understood at that time. We take a venous blood sample from the patient, before treatment, to determine an exact genetic expression affecting the pro-tumor activity and anti-tumor activity, utilizing the Bax/BcL2 ratio. Since p53 gene expression regulates telomerase activity, we had concluded that we may also define a p53/telomerase ratio and then use it for diagnosis and prognosis. We then prescribe the appropriate treatment according to the results. If WT p53 is overexpressed and it down-regulates telomerase enzyme activity, then the cancer tumor is much less resistant and more sensitized to chemotherapy.

We started testing p53/telomerase activity only a couple of years ago, but so far, we have collected many interesting cases. We then perform a second test (when possible) to verify the effect of our treatment on the expression of the various genes included, and then observe the results. Some patients even after remission continue with regular testing even after several years for purposes of prevention and monitoring recurrence. Often the results have shown a condition of high-risk recurrence where we immediately modify the patient’s regimen with appropriate treatment. This is the best way to handle cancer disease and especially prevent any recurrence. Of course, I performed very extensive research and study into the many roles of telomerase in both aging and cancer, especially on the new link between p53 and telomerase and its application in cancer.

I was highly motivated to research which natural compounds had the best efficacy to inhibit telomerase activity while applying the knowledge I gained years ago about restoring mutant p53 to the WT p53 tumor suppressor gene, using selected natural compounds.

In the presence of mutant p53 and highly activated telomerase, we definitively need to first reactivate the gene or the production of normal protein over mutated protein. This is more complicated than only increasing the p53 gene activity. Many natural compounds can stimulate p53 gene activity increasing apoptosis and regulate telomerase, but not all-natural compounds can reverse p53 mutation; yet, I have been able to successfully reverse it. Once again please refer to my previous articles describing in detail the list of the natural agents that have demonstrated efficacy to target both apoptosis and telomerase,⁵⁸ or interfere with glucose transport.⁵⁹ However, this topic is too involved for this article. We will just provide the name of the most important agents with some references but will later offer more details and interesting figures for the reader in my blog along with complete molecular markers clinic case reports with a full explanation. Again, this all requires considerable space; but in summary, it’s very important for doctors to understand how to more effectively handle a cancer case and see how applied therapy is currently functioning along with improvement of genetic status.

Today we have ample scientific proof from multiple targeted cancer therapies utilizing curcumin and genistein, which induce apoptosis; activate the immune cells; inhibit NF-κβ, HER-2/Neu, and EGFR; down-regulate BcL2 and survivin; upregulate Bax; decrease COX2 activity; activate caspases; and stimulates the immune system.⁶⁰ Most important is to note that both curcumin and genistein have strong properties to inhibit telomerase activity by decreasing the level of TERT.^61-63 Both curcumin and genistein may kill CSCs more effectively than chemotherapy.^64,65 This explains why for many years I have included liposomal curcumin and genistein in my cancer protocols together with rice bran arabinoxylan compound (RBAC), a strong biological response modifier that has special properties to activate NK cells. The reader can refer to my last article in the Townsend Letter (August/September 2019).⁶⁶ Besides being known as a strong immunomodulator, some new studies have shown that RBAC improves the Bax/BcL2 ratio along with radiotherapy.⁶⁷ You can use these three compounds together in your cancer protocol and optionally include an anti-angiogenic therapy like C-Statin. This extract is made from a naturally occurring plant (bindweed) that contains a proteoglycan molecule with strong angiogenic properties. You may observe how a tumor can decrease in size and/or eliminate metastasis. (See my TL article “How to Approach Cancer Patients, Diagnostic and Treatment.” August/Sept 2018;68-73.) Other natural compounds have shown efficacy in repressing telomerase activity as well as targeting other cancer mechanisms such as apoptosis, including resveratrol,⁶⁸ green tea polyphenols, epigallocatechin-3-gallate,⁶⁹ allicin,⁷⁰ sulphoraphane,⁷¹ silymarin,⁷² quercetin,⁷³ and genistein.⁷⁴

Examples with a Ratio of p53 Gene and Telomerase Activity

Here we present three patient case examples. These are incomplete concerning other apoptotic and anti-apoptotic genes (due to space limitations). I plan to show more detailed complete case reports with an in-depth explanation,along with more details about the survivin gene and its relation with p53 and cancer in my blog and on my website.

Clinical Case 1: Female, 66 years old, a medical doctor living and practicing in the US with breast cancer remission after surgery and chemotherapy. A very emotive person, under high-stress, who has anxiety. We started her on a better dietary style, and she practices meditation and relaxation. The test was done several months after she started my suggested treatment and diet. The last test was taken in October 2019.

• p53 gene expression:  6116 units/ml of plasma
• p53 normal protein level: 1520 units/ml of plasma. Reference range: 0.1-1.00 unit
• p53 mutated protein level: 28.5 units/ml of plasma. Reference: (N.D. Trace)
• p53 misfolded protein: 500 units/ml of plasma. Reference: (N.D. Trace)
• Telomerase activity: 6816 units. Reference (N.D. Trace)
• The ratio between p53 gene expression and telomerase gene expression:  0.9 (Reference range 1.0)

The p53 gene expression is highly activated together with a very high level of normal p53 protein probably due to the applied therapy; many damaged precancerous cells were destroyed as indicated by the test. However, some cancerous cells started to produce mutated protein and a high level of misfolded protein that can trigger glycolysis. It also may compromise the destruction of some populations of cancer cells through apoptosis. The p53/telomerase ratio is a little bit lower but not enough at the moment to create very resistant cancer cells. The apoptosis in process is highly activated. However, with time, if not improved together with the elimination of mutated and misfolded p53 protein, she may develop resistant cancer cells and increase the risk of recurrence. However, through April 2020 the patient remains in remission. (See more details in my blog: NaturopathicOncology.blogspot.com)

Clinical Case 2: Female, a 38-year-old pharmacist living on the Island of Madeira, was diagnosed with lymphoma but has refused chemotherapy. She went to Germany to receive a special dendritic cell vaccine and ozone therapy treatments. Her March 2019 test results follow:

• p53 gene expression:  380 units/ml of plasma
• p53 normal protein level: N.D.
• p53 misfolded protein level: 8.8 units/ml of plasma
• p53 mutated protein: 13.2 units/ml of plasma
• Telomerase activity: 3108 units/ml of plasma
• The ratio between p53 gene expression and telomerase activity:  (N.A.) 

Here we cannot determine a ratio with these results since the p53 gene is too low compared to the telomerase activity. Even if it can be calculated as 0.122, the laboratory mentions this result as too low to be meaningful. Also, together with a high expression of BcL2 and survivin gene along with a very low Bax/BcL2 ratio, it shows the presence of cancer cells that are resistant to destruction (see more details in the blog). 

Showing p53 gene expression that was too low and producing no WT p53 (normal) protein but only mutated and misfolded protein can trigger glycolysis and inflammation that can stimulate cancer cells.  There is an increasing population of cancer cells with active telomerase and only a small fraction had been destroyed. Because of the high activity of the telomerase compared to the p53 gene activity, many cancer cells can turn into CSCs. Here only a small fraction of pre-cancerous/cancerous cells were destroyed through the genes; however many cancer cells may be destroyed via the immune cells, especially by NK cells, which have increased their activity after the treatment in Germany as observed in the report from the clinic. So, the immune system and especially the NK cells are an alternative to destroy cancer cells when tumor suppressor genes alone are not efficient.  

Clinical Case 3:  Male, 16 years old diagnosed with Ewing sarcoma. This is a very difficult case that I treated for seven years but with very good results so far. Surgery could not remove the total tumor localized on the spine. The boy was subjected to several surgeries, chemotherapy, and radiotherapy yet improved considerably with our treatment. Recently we performed molecular markers testing, including telomerase, to facilitate a better prognostic and possibly prevent any recurrent cancer activity. As of the last scan, the remaining tumor tissue was inactivated.

• p53 gene expression: 5915 units/ml of plasma
• p53 normal protein level: N.D.
• p53 misfolded protein level: N.D.
• p53 mutated protein: 20 units/ml of plasma
• Telomerase activity: 4388 units/ml of plasma
• The ratio between the p53 gene and telomerase activity: 1.3 

The patient continued taking my treatment for the past seven years, which is a success. The high p53 gene activity (before: 1134) is probably from the applied treatment, but no normal p53 protein was produced, only mutated protein. However, many cancer cells were destroyed through the highly activated Bax and P21 gene expression. (See my blog) The ratio p53/telomerase is good 1.3; p53 gene expression maintains a lower telomerase activity and an inactivated tumor. However, the result of the test showed the presence of cancer cells somewhere in the body; the patient continues with check-ups and the risk of tumor reactivation still exists (We still closely follow the case).

Discussion

The article has shown that the metabolic cause of cancer is associated with the Warburg effect and mitochondria dysfunction, which allows cancer cells to switch to the glycolysis pathway. The p53 gene plays a key role in inhibiting glycolysis, inducing apoptosis, and as a new function may inhibit the telomerase activity, which today gains considerable interest as a target against immortal cancer cells. Cancer disease is no longer a mystery, but a disease that can be treated differently. Thankfully, at last, some selected natural compounds and other foods have demonstrated properties that target p53 and telomerase, as presented in the article.

Complete References

More information on cancer can be seen from my last lecture in Europe, “How to Understand and Treat Cancer with Modern Methods” (Zagreb, Croatia; February 28, 2018), on Slideshare: http://www.slideshare.net/sheldonstein.

The reader may also receive an in-depth understanding by viewing my 2019 Medicine Week (Baden-Baden) presentation “A New Modern Way to Approach Cancer” on Slideshare:

Prof Serge Jurasunas Upcoming Presentation – Oct 30 2019 Baden Baden from Sheldon Stein