We've discussed in the past the possibility that zinc supplementation can change the conformation of mutant p53 back to a more normal state. There is now evidence that oral zinc supplementation (in mice) can also activate non-mutant p53 and sensitize tumors to chemotherapy (in this study the chemotherapy was Adriamycin (doxorubicin).
The beneficial effect of Zinc(II) on low-dose chemotherapeutic sensitivity involves p53 activation in wild-type p53-carrying colorectal cancer cells
Might not be a bad idea to take higher dose zinc (100 mg) on the days surrounding chemotherapy, with the caveat that the effects of p53 in response to doxorubicin may not be the same in response to temozolomide.
Continuous intake of 40-50 mg zinc daily is said to be safe.
An additional amazing piece of evidence, is that both U251 (mutant p53) and U87 (wild-type p53) GBM cell lines were mostly positive for unfolded mutant-type p53 conformation. U87 cells were found to have four-fold increased levels of metallothionein 3. Metallothioneins are zinc-binding proteins. This zinc-binding activity of metallothioneins likely leads to unfolded mutant-like p53 proteins, even in the absence of a TP53 mutation!
High metallothionein predicts poor survival in glioblastoma multiforme
I've got low grade Oligodendroglioma, 1p/19g deleted, IDH1 mutation, CIC mutation and apparently TP53 mutation. This is extremely rare. I wonder if there was a mistake? Is there anyway of measuring the p53 protein levels without having to do a genetic test again
ReplyDeleteYes, p53 protein levels can be assessed using immunohistochemistry. From what I can gather, PAb240 antibody detects p53 in mutant-type conformation, while PAb1620 antibody detects normal-type conformation. Other antibodies detect total p53 levels (mutant and normal).
ReplyDeletep53 proteins can show a mutant-type conformation, even in the absence of TP53 mutations. This can be due to factors such as metallothioneins (causing intracellular zinc deficiency, see above study) or to other factors such as hypoxia.
http://www.jbc.org/content/287/4/2907.full.pdf+html
Was your tumor tissue ever tested for levels of p53 protein (as opposed to genetic testing for TP53 mutation)?
It was just the FoundationOne test.
DeleteFor those who want to dig deeper on p53 mutations this page is a good place to start:
ReplyDeletehttp://p53.free.fr/our_work/structure.html
According to this, TP53 mutations at codon 248 and 273 retain a wild-type conformation and are recognized by the PAb1620 antibody, while mutants at codon 175 have the altered conformation recognized by PAb240 antibody.
But as we've seen the conformation of the p53 protein can be altered by non-genetic factors, such as the abundance or deficiency of zinc inside the cell, and oxygen concentrations.
Another question is how would zinc supplementation affect disulfiram therapy, or vice-versa, as disulfiram is also a chelator of zinc, in addition to copper.
ReplyDeleteHello all,
ReplyDeleteI recently decided to add zinc (50mg/day) to my diet, since it is cheap and I guess it can't hurt. I found few options/forms of zinc supplementation, one of them being Zinc Picolinate (for example http://www.iherb.com/Now-Foods-Zinc-Picolinate-50-mg-120-Veggie-Capsules/878 ).
In one of the studies from 1987 ( https://www.ncbi.nlm.nih.gov/pubmed/3630857 ) I found this:
"At the end of four weeks hair, urine and erythrocyte zinc levels rose significantly (p less than 0.005, p less than 0.001, and p less than 0.001) during zinc picolinate administration. There was no significant change in any of these parameters from zinc gluconate, zinc citrate or placebo administration."
If not stated otherwise, I think most of zinc supplements are in form of zinc gluconate. Any thoughts on these different forms - gluconate vs. picolinate?
Regarding zinc dosage:
ReplyDeleteFrom https://ods.od.nih.gov/factsheets/Zinc-Consumer/
"Rcommended ammount of zinc per day
Adults (men) 11 mg
Adults (women) 8 mg
With upper limit oz zinc per day being
Adults 40 mg
Signs of too much zinc include nausea, vomiting, loss of appetite, stomach cramps, diarrhea, and headaches. When people take too much zinc for a long time, they sometimes have problems such as low copper levels, lower immunity, and low levels of HDL cholesterol (the "good" cholesterol)."
I pasted this because I think 50mg/day is standard dose used by people here. Any thoughts?
The page on zinc at examine.com is worth a read:
Delete"Superloading zinc by taking up to 100mg zinc a day is confirmed to be safe in the short term (2-4 months), but because this dose is higher than the 40mg Tolerable Upper Limit (TUL) of zinc, prolonged superloading is not advised. Zinc’s intestinal uptake is hindered by other minerals, including Calcium, Magnesium, and Iron, since they all use the same transporter. If the transporter’s uptake limit (800mg) is exceeding between these four minerals, absorption rates will fall. Taking less than 800mg of these four minerals at the same time is fine."
https://examine.com/supplements/zinc/
DeleteThanks!
Delete