The P53 tumor suppressor gene: understanding P53-based anticancer therapies utilizing dietary agents.
The P53 tumor suppressor gene, which has been dubbed both the "Guardian of the Genome" (Lane 1992) and Science "Molecule of the Year," is directly involved in the initiation of apoptosis and programmed cell death, to prevent an accumulation of abnormal cells. However, apoptosis evasion is a characteristic feature of human cancers that promote tumor formation and progression. (1) Presently, P53 is known to play a key role in practically all types of human cancers, and the mutation or loss of P53 gene function can be identified in more than 50% of all human cancer cases worldwide. (2)
Frequency of P53 Mutations
70% in lung cancer
60% in cancers of colon, head, neck, ovary, bladder
45% in stomach cancer
35%-40% in breast cancer
Recent data have shown that, in addition to losing transcriptional function, mutant P53 gains oncogenic functions termed GOF (gain of function) that drive cell migration, invasion, and metastases. (3,4) The notion for mutant P53 GOF theory is supported by recent studies using mutated P53-blocked mice which display a broader tumor spectrum, increased aggressiveness and metastatic potential as compared with their P53-null counterparts. (5,6) Similarly, in human cancers mutant P53 expression has been linked with a poor prognosis. (7) Therefore, mutant P53 function raises the possibility that the mutant protein may be a good target for designing novel therapies.
The P53 pathway seems to play a critical role in therapeutic response both as a diagnostic and marker in the prognosis of therapeutic treatment effects.
The inability of most cancers to undergo apoptosis in response to appropriate stimuli is a key cause of treatment failure, presenting one of the major yet unsolved problems in oncology. (8)
Programmed cell death, called apoptosis, is a fundamentally important process that prevents an accumulation of genetically abnormal cells. Apoptosis induction often appears to be related to the production process of P53 protein. This follows the activation of the tumor suppressor gene as a stress response to any DNA damage within a cell nucleus. (9) In normal, unstressed cells, P53 is expressed at a very low level; the half-life of the protein does not exceed 20 minutes.
Active P53 binds to target DNA and determines the choice between triggering cell cycle arrests at a checkpoint to allow DNA repair or activating a special molecular pathway leading to the self-destruction of a cell through apoptosis. Both alternatives provide any organism with genetic stability.
The critical role of P53 is made evident by the fact that it is mutated in approximately 50% to 70% of all human cancers. In fact, P53 is the most commonly mutated gene in human cancer.
In human malignancies, very often there are mutations or a loss of alleles in the gene located on the chromosome 17P. More than 500 mutations in the P53 gene have been discovered, although they are not equal in terms of biological activity.
The mutated gene in transformed cells leads to protein confirmation changes and the accumulation of very stable mutant forms of P53 in the nucleus. All types of mutated P53 are likely to be ineffective in maintaining a nontumorigenic cellular phenotype when compared with a wild-type P53.
Wild-type P53, a nuclear phosphoprotein, has been shown to be a sequence specific transcription factor which induces the expression of P21, WAF1/C1 P1/Sdi-1, leading to a G1 arrest checkpoint to step up repair before DNA replication and contributes to normal cell proliferation; unless DNA replication is successful, the cells will be induced to undergo apoptosis. (10)
However, during a stress response from its P53 gene to any damage, recent findings suggest that P53 induces apoptosis by transactivating expression of the BAX gene mRNA to increase BAX protein and simultaneously inhibit the function of Bcl-2.n RNA proteins are homologs, though BAX acts as an accelerator of apoptosis while Bcl-2 serves to prolong survival. (12)
This suggests that P53 mutation not only serves to inactivate the proapoptotic P53 pathway but may also play an additional role in tumor progression. Mutant P53 itself provides a selective advantage to tumor cells and promotes tumor growth. Recent data suggest that expression of mutant P53 is not the equivalent of P53 loss, wherein mutant P53 can acquire new functions.
Bcl-2 activity upregulates in many types of cancer and correlates with cancer cell resistance to a wide spectrum of chemotherapy agents.'3 Overexpression of the antiapoptotic Bcl-2 proteins blocks cytochrome C release in mitochondria in response to a variety of stimuli, whereas the proapoptotic BAX protein releases cytochrome C that in turn activates an apoptotic cascade, while the loss of BAX is associated with tumor progression and shorter survival in metastatic breast cancer. (14)
BAX was the first identified P53-regulated, proapoptotic Bcl-2 family member. P53-responsive elements have been unequivocally identified in the BAX gene. (15) BAX is specifically required for PUMA (p53-upregulated modulator of apoptosis)-mediated apoptosis, and it also participates in the death response as an indirect target of P53 through PUMA and Noxa, both implicated in P53-dependent apoptosis. (16)
Some studies show that the loss of BAX is responsible for nearly half of the accelerated tumor growth in brain tumors that are related to loss of P53 function. (17) BAX is inactive in approximately one-third of invasive breast cancers; in a study of 119 women with metastatic breast cancer, it was found that patients whose tumors had lost BAX activity had poor responses to combination chemotherapy, faster time to tumor progression, and shorter overall survival. (18)
This may suggest that turning on this proapoptotic gene may be important for chemotherapy response, wherein one of the factors that can regulate BAX gene activity is the P53 tumor suppressor gene, which also simultaneously inhibits Bcl-2 during the process of apoptosis. Nevertheless because BAX proteins antagonize Bcl-2 antiapoptotic function, it is likely that the Bcl-2/BAX balance ratio determines both the susceptibility of a cell to apoptosis and therapeutic response to apoptosis stimuli. (19)
If apoptosis signaling is not initiated by nuclear P53 and/or the presence of a mutated P53 gene, loss of BAX, and overexpressed Bcl-2, this allows some cancer cells to divide unchecked after radiation or chemotherapy treatment, associated with cancer cell resistance, increased rate of tumor recurrence, and shorter patient survival. (20)
Another profound feature of malignant cells is their ability to induce angiogenesis necessary for tumor growth. Again, there is a clear correlation between mutant P53 GOF that facilitates angiogenesis by increasing the expression of VEGF, via interaction with E2F1 that induces the expression of ID4, which in turn promotes the expression of proangiogenic factors such as IL and GROa, thus eventually leading to increasing angiogenesis in cancerous tissues. (21,22) Other novel functions of mutant P53 GOF are shown through the activation of specific target genes EGFR/1, RAS, Myc, and interference with the TGFB growth arrest control pathway, downregulation of the E-cadherin cell-cell adhesion molecules to enhance motility, and tumor cell migration and invasion. (23)
We have new clues and important conceptualizations which indicate that tumors cannot be viewed simply as an uncontrolled proliferative mass, but rather as a cellular community, interacting with a microenvironment. (24,25) This is why targeting mutant P53 remains an urgent need to improve cancer treatment by increasing a cancer cell's sensitivity to apoptosis.
Targeting mutant P53 and restoring the wild-type function of P53 tumor suppressor gene in tumor cells would be of potential therapeutic benefit and an attractive strategy for anticancer treatments. (26-27) Upon restoration of P53 transcriptional activity, the apoptosis pathway would predominate.
Many cancer cells escape apoptosis and become resistant to chemotherapy radiation or from destruction by the immune cells by endogenous cytotoxic T-cells and natural killer (NK) cells. If the oncogene Bcl-2 is highly expressed it confers greater resistance to cancer cells from attacking immune cells, increasing the urgent need for effective cancer therapies.
Furthermore, some of the P53 apoptosis targets such as BAX, PUMA, Noxa, and P21 could potentially be used as targets for gene therapy to increase the effectiveness of chemotherapy.
Dietary Agents that Induce Apoptosis with Chemo Preventive Effects
A large number of dietary agents can exert effects on the human genome either directly or indirectly to modulate gene expression. Extensive research during the last half-century demonstrated that numerous agents identified from fruits and vegetables can interfere with several signaling pathways and were validated as apoptosis inducers in research experiments.
These dietary agents include well-known, well-documented substances recommended for cancer prevention and therapy, such as curcumin (turmeric), resveratrol (grapes), genistein (soybean), capsaicin (red chili), ellagic acid (pomegranate), caffeic acid and phenyl ester (propolis), polyphenols (green tea), catechin (green tea), and indole-3-carbinol (cruciferous vegetables). (28-35)
They have all clearly accumulated evidence demonstrating their efficacy to induce apoptosis by modulation of the P53 independent pathway, BAX, BAK, targeting the antiapoptotic proteins, Bcl-2, and survivin gene so as to potentialize a chemotherapy/radiation regimen. Curcumin, for instance, has been found to inhibit the activity of NF-kB and Bcl-2, and increase P53 activity as well as sensitize cancer cells to cisplatin- and Taxol-induced apoptosis. (37) The combination of 5-Fu and genistein enhances therapeutic effects in colon cancer through the COX-2 pathway. (38) Genistein combined with docetaxel or gemcitabine significantly inhibited Bcl-2/ Bcl-xL, survivin, and induced P21 WAF1, suggesting that combination treatment regulates the important molecules in the apoptotic pathway. (39,40) Green tea and black tea cause induction of apoptosis accompanied with upregulation in BAX and a decrease in Bcl-2 proteins in prostate cancer cells. (41) Capsaicin-caused apoptosis in prostate cancer cells shows an increase of P53, P21, and BAX. (42) Curcumin downregulates the apoptosis suppressor proteins Bcl-2 and Bcl-xL in several cancer cell lines, thus increasing apoptosis overall. (43)
In human breast cancer cells, curcumin induces apoptosis through P53-dependent BAX induction; curcumin, resveratrol, and green tea polyphenols are also known to downregulate the expression of apoptosis suppressor proteins such as Bcl-2 and Bcl-X in several cancer cell lines. (44)
In human prostate carcinoma LNCaP cells, treatment with EGCG-induced apoptosis was associated with stabilization of P53, with an accompanying downregulation of NF-kB activity resulting in a decreased expression of the antiapoptotic Bcl-2. Overall dietary agents synergize with chemotherapeutic drugs, thereby reducing the toxicity of chemotherapeutic agents. (45)
Numerous studies continue to report that resveratrol exerts its anticancer effects by causing cell cycle arrest and inducing apoptosis in many different cancers. (46) These include colon adenocarcinoma cells (Caco-2), esophageal carcinoma cells, medulloblastoma cells, the highly invasive and metastatic breast cancer cell line MDA-MB-231, melanoma cells, pancreatic carcinoma cells, esophageal squamous carcinoma cells, and lung cancer cells.
A complete document concerning the modulation of apoptosis by active compounds for cancer therapy and their synergy with chemotherapeutic agent is available at www.sergejurasunas.com.
Deregulation of P53 has enormous influence on carcinogenesis as mutant P53, which can induce an increased epigenetic instability of tumor cells, facilitating and accelerating tumor evolution.
An increasing body of investigation has shown that inhibitor of apoptosis protein (lAPs) as Bcl-2, survivin, and so on, is now seen as diagnostic markers for early-stage malignancy and novel prognostic markers. (47) In addition these molecules have been validated as therapeutic targets. Accumulated evidence clearly indicates that dietary agents may play a critical role by targeting P53 and IAPs and improve chemotherapy regimen. Despite significant advances in cancer diagnosis and therapy, there is still little progress in the treatment of advanced disease.
Most modern medicines currently available for treating cancer are very expensive, toxic, and less effective in treating the disease. Therefore new effective ways to treat cancer have become a priority. Thus, one must investigate further in detail, dietary agents derived from natural sources without toxicity. Hopefully, they will find a place in the clinical management of patients with malignancy.
We have been measuring the activity of P53 pathway, BAX, Bcl-2, survivin, and P21 gene expression with a large number, variety, and grades of cancer patients, developing a targeting therapy that could restore mutant P53 to a normal wild-type function as a first step after gaining results to modulate BAX, inhibit the Bcl-2 and survivin antiapoptotic proteins. The targeting therapy includes dietary agents such as curcumin and other compounds empirically experimented upon by the author. It includes an extract of fish oils rich in oligopeptide, that contain short-chain amino acids shown to have efficiency to target mutant P53, fermented chlorella in tablets rich in vitamins, minerals, and nucleic acids. (48) The fermenting process increases the level of nutrients and absorptive power. Finally, an antioxidant compound was derived from modified vegetables and seeds, with low molecular weight having SOD-like activity. (49)
This targeting therapy, known as PSJ-53 therapy, had been first utilized in experiments to restore mutant P53 and proved by P53 gene expression and P53 protein testing. Later experiments in modulating BAX gene expression and targeting Bcl-2 and survivin antiapoptotic proteins were shown to potential ize the efficiency of chemotherapy and radiation. (50) Survivin, a unique member of the IAPs, inhibits caspase-7 and -9 and promotes both cell proliferation and angiogenesis. (51) Measuring and targeting survivin remains a major goal in response to antineoplastic agents. (52)
We present three cancer cases with blood analysis reports of P53 gene expression and mutated protein levels before and after the treatment, along with two cases with complete figures of the proapoptotic and antiapoptotic genes before and after treatment.
1. a case of multicancer recurrence.
2. remission of breast cancer
3. pancreatic cancer
4. recurrence of colon cancer
5. lung cancer
P53 pathway activity and other proapoptotic and antiapoptotic genes were evaluated by measuring protein concentration and the level of P53 gene expression, Bcl2, BAX, survivin, and P21 in the same peripheral venous blood obtained from patients in the clinic.
The enzyme-link immunosorbent assay (ELISA) was used together with the polymer chain reaction (PCR) to evaluate P53, BAX, survivin, and P21 gene expression levels and for the qualitative detection of P53 protein. Blood samples were collected in sterile tubes and sent to a laboratory specializing in molecular marker tests, which offers complete reports and discussion about each test. Survivin/P21: 0.53
We have clearly demonstrated that mutant P53 can be targeted together with other proapoptotic and antiapoptotic genes using dietary compounds, which for many patients has been proved with many scientific examples. This is only one example and not the publication of cancer cases followed over a 1- or 2-year period as we have done with many patients. This child has now been treated for over 2 years with excellent results, and has taken 5 blood analyses, which each time indicated what treatment should be done. However, my last article in the Townsend Letter 2014 showed complete cases relative to breast cancer with molecular marker testing done over a 1-year period and more. Step by step it showed improvement and the normal balance between the proapoptotic and antiapoptotic genes. (50)
New avenues are now focusing on targeting apoptosis in cancer, which include oncogenes, Bcl-2, and survivin that increases cancer cell resistance to chemotherapy/ radiation regimen, while scientific literature today has already accumulated thousands of articles on laboratory reports, theories, and studies.
We urgently need to put into clinical practice what we have discovered and learned. Targeting P53 and other genes remain one of the greatest challenges in the treatment of cancer. We have been working now for over 8 years with molecular markers as a diagnostic, prognosis, and follow up to treatment, selected the appropriate bioactive dietary compounds or anticancer agents, exceeding 1000 cases, blood tests, and successes. This may be an incentive for more doctors to venture into this new direction in order to achieve more beneficial results with patient treatment, especially in cases where we can verify the ones who would be refractory to chemotherapy and have a poor response. It is always best to first check through patient testing, to determine whether or not chemotherapy would be beneficial.
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Professor Serge Jurasunas, a frequent Townsend Letter contributor, will be the featured speaker at the Physician's Round Table Conference to be held in Tampa, Florida, January 29-31, 2016, together with other well-known integrative cancer doctors. He will present two lectures: "Health and Disease Begin in the Colon, As Seen through Iridology" (he will be signing his new expanded book on the subject), and "How to Understand Cancer from a Molecular Basis." He will show how cancer can be diagnosed earlier on and then treated with dietary agents.
For additional information, contact Peerobmagazine@aol.com.
Serge Jurasunas is an internationally well-known doctor of naturopathy and alternative medicine with over 40 years of experience in the treatment of cancer. He is developing innovative therapies in cancer treatment and is a pioneer in live blood analysis, dried blood oxidative stress, and iridology.
Dr. Jurasunas is busy working with P53 tumor suppressor gene and other molecular markers testing related to cancer patients and patients with high risk of cancer.
For more information and to learn about cancer treatment, molecular markers, and clinical cases at Holiterapias Clinic, please visit www.sergejuraunas.com; e-mail: info@ sergejurasunas.com; phone: +351 213471117.
Table 1: Effects of PSJ-53 Therapy on the Tumor Suppressor P53 Pathway M: Case of Multiple Cancer Recurrence P53 protein level units/ml of plasma No Date of Wild P53 Ref. Mutated P53 blood sample range * <0.33 units/ Ref. range collection ml of plasma ND ** 1 2 Feb 2009 ND ** 26.1 2 18 May 2009 16.8 ND ** 3 21 Sep 2009 156.0 ND ** No P53 gene (wild expression level Ref. range * < [10.sup.6] copies/ml of plasma 1 2.7 x [10.sup.5] 2 8.9 x [10.sup.11] 3 1.5 x [10.sup.13] No Comments 1 The blood sample was collected prior to PSJ-53 therapy 2 The blood sample was collected after a 3 month course of PSJ-53 therapy 3 The blood sample was collected 4 months after completion of the PSJ-53 therapy during which time no further treatment was given Table 2: F: 48 Years Old: Breast Cancer--Breast Cancer in Remission 2009 P53 protein level units/ml of plasma No Date of Wild P53 Ref. range Mutated P53 blood sample * < 0.33 units/ml of Ref. range collection plasma ND ** 1 2 Feb 2010 ND ** 52.5 2 19 Apr 2010 10.99 ND ** No P53 gene (wild Comments expression level Ref. range * < [10.sub.6] copies/ ml of plasma 1 52.245 The blood sample was collected prior to PSJ-53 therapy 2 170.000 The blood sample was collected after a 2 month after completion of the PSJ-53 The results clearly show the presence of mutated P53 prior to PSJ-53 therapy. However, after 2 months of the treatment, we reversed the mutant P53 to a normal wild-type function, associated with an increase of the P53 therapy gene expression and protein level during this period of time. Table 3: F: 56 Years Old--Pancreatic Cancer--5 Years of Remission P53 protein level units/ml of plasma No Date of Wild P53 Ref. Mutated P53 P53 gene (wild blood sample range * <0.33 Ref. range expression level collection units/ml of ND ** Ref. range * < plasma [10.sup.6] copies/ ml of plasma 1 4 May 2009 ND ** 52.5 52.245 2 4 July 2009 10.99 ND ** 170.000 3 17 Nov 2009 67.4 ND ** 1.2 x [10.sup.6] No Comment 1 The blood sample was collected prior to PSJ-53 therapy 2 The blood sample was collected after a 2 month after completion of the PSJ-53 therapy 3 The blood sample was collected after a 4 month after completion of the PSJ-53 therapy The results clearly show the presence of mutated P53 prior to the PSJ-53 therapy. However, after 2 months of therapy followed by 4 months of treatment, we reversed the mutant P53 to a normal wild-type function, and gradually the P53 wild protein production rose to a high level, leading to increased self-destruction of cancer cells. Table 4: M: 81 Years Old: Recurrence of Colon Cancer--Liver Metastases The patient refused chemotherapy but agreed to take some radiation therapy. He was sent by his medical doctor to take molecular markers testing to first check whether radiotherapy would be efficient. P53, BAX, or P21 should be active and sensitive to radiation, and increase selfdestruction of cancer cells. New Reference range: P53 protein level wild//0.10//1.00 units/ml of plasma P53 gene expression: 10-50 units/ml of plasma Bcl-2 gene expression: 10 units BAX gene expression: 10-100 units Survivin gene expression: 10 units P21 gene expression: 10-50 units P53 protein level units/ml of plasma No Date of blood Wild P53 Ref. Mutated P53 P53 gene (wild sample range * <0.33 Ref. range expression collection units/ml of ND ** level Ref. plasma range * < [10.sup.6] copies/ml of plasma 1 1 Mar 2011 ND ** 10.88 ND ** 2 11 Jul 2011 ND ** ND ** 1.180 No Bcl-2 BAX Survivin P21 1 390 ND ** 129 ND ** 2 ND ** 409 ND ** ND ** The results clearly show after 4 months of treatment a significant improvement and reversal of the mutant P/53 tumor suppressor gene. However, the P53 gene didn't induce the level of normal protein (often because of a blockage of PUMA). BAX gene expression is now active as a pathway to destroy cancer cells and the oncogene Bcl/2 and survivin are not active due to the applied treatment. Therefore the new pattern showed that cancer cells were destroyed and that radiotherapy would be efficient, increasing the destruction of cancer cells. The first report showed Bcl/2 and survivin were slightly active (at risk) but after the treatment were totally inhibited, which contributed to increase the efficiency of chemotherapy/radiation regimen. After radiation therapy and further treatment with natural compounds, the patient was free from liver metastases. Table 5: M: 50 Years Old--Lung Cancer P53 protein level units/ml of plasma Date of blood Wild P53 Ref. Mutated P53 P53 gene (wild No sample range * <0.33 Ref. range expression collection units/ml of ND ** level Ref. plasma range * < [10.sup.6] copies/ml of plasma 1 7 Jan 2013 ND ** 16.26 ND ** 2 11 Mar 2013 0.1 ND ** 3 P53 protein level units/ml of plasma Bcl-2 BAX Survivin P21 No 1 340 330 1.028 552 2 2 5 5 4.527 Ratio of the 1st Analysis Bcl/BAX: 0.89 Survivin/P21:0.53 Ratio of the 2nd Analysis Bcl/BAX: 2.5 Survivin/P21: 905.4--too high to make a ratio The results clearly show after 2 months with PSJ-53 therapy that we reversed mutant P53 to a wild type function, but P53 protein was produced only to a certain extent. However, we have targeted Bcl-2 and especially the high expression of survivin to a normal range and eliminated resistance in some population of cancer cells and increased the selfdestruction of cancer cells through chemotherapy-radiation with a resultant decrease in lung nodule size. P21 gene expression is very highly active (4.527) and promotes the self-destruction of cancer cells. P21 is a P53-independent channel to apoptosis and can be independent of P53 activated by another channel such as the TGF-B. P21 is very sensitive to radiation in destroying cancer cells. Table 6: F: 8 Years Old--Glioma Postponed chemotherapy after three surgeries and poor results. P53 protein level units/ml of plasma No Date of Wild P53 Ref. Mutated P53 P53 gene (wild blood sample range * <0.33 Ref. range expression collection units/ml of ND ** level Ref. plasma range * < [10.sup.6] copies/ml of plasma 1 6 Jan 2013 0.2 ND ** 1.344 2 11 Mar 2013 16.4 ND ** 820 No Bcl-2 BAX Survivin P21 1 2.066 1.714 1.734 2.192 2 131 ND ** ND ** 229
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|Date:||Aug 1, 2015|
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