A metabolic therapy for cancer - correcting p53 deficiency?

A metabolic therapy for cancer - correcting p53 deficiency?

P53 is deficient in many cancers; it normally regulates some 500 gene pathways. Increasingly, natural compounds such as olive oil, polyphenols, IP-6, melatonin, ashwagandha, CAPE, berberine and glucose control have been shown capable of restoring p53 function. 

As we explained in our review TP53, p53 and cancer, there is a lot of conjecture and even misreporting on this subject. Several major articles report that the TP53 gene is mutated in 50% of cancers. This is inaccurate. TP53 refers to Tumour Protein 53, p53 is protein 53. It is rarely mutated. It simply goes AWOL.It is missing in 96% of ovarian cancer and almost all sarcoma cancers. Hitherto the problem has been an inability to accurately measure levels. It is also called 'the Guardian of the Genome', and 'the Guardian of the Mitochondrial genome' (mitochondria contain 37 genes, which are easily, metabolically damaged - p53 can cross into the mitochondria and return stability (1).

A lack of testing for deficient p53

In prostate cancer it was thought to be a problem only in metastatic prostate cancer, but as diagnostic tests have improved, a deficiency in p53 has been found common in newly diagnosed patients with disease as well. The DATAR test can show it, but only for breast and prostate cancers. The new more widely used Guardiant360 test does not even include p53 in the 40 genes it tests. How odd if it is 'mutated' in 50% of cancers!

Why target one pathway when p53 regulates 500?

P53 is not a ‘mutation’ in your DNA. It is a deficiency of a protein, driven by a poor metabolism.

Love him or hate him, Max Gerson explained what was known nearly 100 years ago about the issue.

Sometimes your cells increase their sodium levels at the expense of potassium. When this this happens your power stations in your cells (mitochondria) can be affected too, and have a buildup of sodium rather than potassium in them. They can run on either, but are meant to run on potassium. If they start running on sodium, with each round of the energy producing ‘Kreb’s Cycle’, the sodium salts produced are more acidic than the potassium salts that should have been produced. This acidity builds up causing inefficiency in the cells. Less oxygen is pulled into the cycle, and less energy is produced.

The metabolism of energy production has hit a downward spiral. Think of your cell as a battery running down; there is not enough energy produced to keep p53 running, and p53 controls many genes including those for a ‘normal’ rate of division. If it switches off it leaves lower energy-requiring genes such as the ras gene in charge and this causes cells to run out of control.

Why might the cells and mitochondria have heightened levels of sodium? Firstly, you could eat a high sodium low potassium diet - refined, processed, packaged foods, sausages, bacon, salami, dried meats, meals with MSG, cheese, chips, bag snacks etc.etc.,

But also, there is a pump on the wall of cells, it requires magnesium to run properly pushing potassium into your cells and kicking sodium out. It can shut down. 40% of women in Britain are deficient in magnesium. Apart from a poor diet - stress, drugs, alcohol and too much dairy can cause this, as can oestradiol or xenoestrogens. Nuts and seeds, pulses, green vegetables, fruits and dark chocolate are good for magnesium.

Gerson believed almost all chronic illness originated because of metabolic problems in the cell and mitochondria. Like Cardiovascular disease, Type-2 diabetes and dementia, cancer is now known to be a metabolic disease after Christine Meyr of Sloan Kettering showed that there are no new cancer causing mutations in your DNA - its the copying process that is faulty - and we already know that poor metabolism causes a build up of homocysteine, that blocks the copying process..

We have research showing that an active p53 directly regulates approximately 500 target genes, thereby controlling a broad range of cellular metabolic processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death (2). Why target one pathway, when you can target 500? For example, when DNA is damaged or mutated, p53 can dispose of it. p53 is itself controlled by regulators such as MDM2. A series of man-made compounds called Nutlins have been used with AML to inhibit MGM2 and restore p53.

P53, metabolic therapy and cancer

Before you go on you really should read:

   i)  TP53, p53 and cancer -  Here

   ii) Cancer - why you’re not doomed - Here

How might you restore p53 and cause cancer cell apoptosis?

i) Diet - You need a diet high in minerals particularly iron, potassium and magnesium and low in sodium. It's called a Rainbow Diet - a colourful Mediterranean Diet. We have research on each of these. For example, Magnesium (and zinc but to a lesser extent) can reestablish p53 control (2) and has been shown to encourage p53 cancer cell apoptosis (3). Extra Virgin Olive oil, fish oils, olive leaf extract, amino acids and polyphenols can do this too (5). Reduce your sodium intake!

Gerson used a diet (and juices) rich in potassium and magnesium; similar to Rainbow diet but more stringent.

One of the most important minerals for oxygenating cells and reestablishing a healthy cellular metabolism is Iodine. It is also an antioxidant and has immunomodulatory powers. It can weaken cancer stem cells and cause cancer cell apoptosis. Iodine has been shown to inhibit Colorectal cancer by restoring p53 levels (9).

A Mediterranean Diet supplemented with CoQ10 restored p53 levels in elderly subjects (11).

ii) Niclosamide - this anthelmintic drug attacks and ‘uncouples’ cells that are p53 deficient with research showing it can reduce tumours by 50% if they are p53 deficient. It inhibits oxidative phosphorylation and stimulates adenosine triphosphatase activity in the mitochondria. One study used 1200 mg, 3 times a day, after a light meal; but there is no ‘Official’ anticancer dose. Ask your supplier.

iii) IP-6 - research on breast cancer, colorectal cancer, prostate cancer and brain tumours has shown that this natural compound from bran can upregulate the p53 and p21 genes. The dose is 800-1000 mg, three times per day between meals.

iv) Resveratrol, genistein, berberine, lycopene, melatonin, green tea, ursolic acid and triptolide (from the Thunder God Vine) all have shown the ability to inhibit MDM2 in vitro and in vivo and help to restore p53. Turmeric has been shown to inhibit MDM2 and stabilise p53 in prostate cancer in vitro and in vivo by researchers at the University of Alabama. The phenols as a group (resveratrol, olive oil and 500 others are top foods for cancer protection and correction are abundant in the Rainbow Diet) all restore p53.

Apigenin, genistein, berberine, gensenosides, saponin, oroxylin A and flavopyridol have all been shown to reduce MDM2 and restore p53 (10)

v) Withanone and Withaferrin from Ashwagandha, Cucurbitacin-B from Bitter Cucumber and CAPE and ARC from honeybee propolis can all restore (6) wild-type p53.

vi) Phenethyl isothiocyanate (PEITC) can reactivate p53 and prevent cancer cell growth (7). PEITC is derived from cruciferous vegetables.

vii) Not wishing to be controversial but Glucose Control has been shown (8) to restore p53. Researchers from Duke's in Carolina have shown that the family of proteins - including p53, p63 and p73 - is involved in glucose metabolism, Glucose homeostasis and regulation by p53 seems a two-way process. Target a fasting blood sugar level of 4. Don't go near Dexamethasone!

viii) Low p53 causes cholesterol to form esters than can lead to a heightened cancer risk. Strong p53 can inhibit the mevalonate pathway, which is responsible for the biosynthesis of cholesterol. 

*****

References

1) p53 as guardian of the mitochondrial genome; Ji-Hoon Park et al; Review FEBS Lett. 2016 Apr;590(7):924-34

2) How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? - Brandon J Aubrey 17 Nov 2017 Nature - https://www.nature.com/articles/cdd2017169  

3) Investigating the Influence of Magnesium Ions on p53-DNA Binding - https://pubmed.ncbi.nlm.nih.gov/28754018/

4) Controlled release of hydrogen by implantation of magnesium induces P53-mediated tumor cells apoptosis - https://pubmed.ncbi.nlm.nih.gov/34820578/ 

5) Anti-Arthritic and Anti-Cancer Activities of Polyphenols: A Review; Muhammed Ali et al; Life (Basel). 2023 Feb; 13(2): 361

6) Comparative computational and experimental analyses of some natural small molecules to restore transcriptional activation function of p53. Seyod Shefrin et al; Current Research and Structural Biology; Volume 4, 2022, Pages 320-331

7) Reactivation of mutant p53 by a dietary-related compound phenethyl isothiocyanate inhibits tumor growth; Nature Published: 03 June 2016

8) Emerging Roles of p53 Family Members in Glucose MetabolismYoko Itahana and Koji Itahana;  2018 Mar; 19(3): 776.

9) Iodine-125 induces apoptosis via regulating p53,; Zhenhuan Ma et al;  2014; 12: 222.

10).Natural products targeting the p53-MDM2 pathway and mutant p53:; Jiang-Jiang Qin et al; Genes Dis. 2018 Sep; 5(3): 204–219.;  

11Mediterranean diet supplemented with coenzyme Q10 induces postprandial changes in p53 in response to oxidative DNA damage in elderly subjects; Fracisco Gutierrez-Mariscal et al; Age (Dordr). 2012 Apr; 34(2): 389–403.

 


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