haidut

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User @Travis made an interesting post recently, in which he specified that polyamines drive cancer progression and that selenomethionine could inhibit polyamine synthesis. The same line of thought has been expressed by Peat, Gerson, Revici, etc - that several polyamines (especially putresine and cadaverine) formed in the gut from decaying food, drive cancer progression. User @burtlancast also talked about it in regards to the Gerson diet.
Cottage Cheese & Fresh Flax Seed Oil Cures Cancer

While I was reading studies on factors that drive cancer progression, I stumbled on an older Russian studies from early 1990s. It has a number of very interesting points. Among them is the statement that the ratio of specific polyamines (putrescine/spermidine) can be used as biomarker for the progression/stage of ANY cancer. Another one is that reducing that ratio is highly therapeutic and may even reverse cancer metastases. Finally, it states that cancer metastases is driven largely by stress (in this case surgical removal of primary tumor), which is a topic on which I will make a separate post altogether.
Btw, this is a Russian study and the polyamine ratio test is not used AFAIK in clinical oncology in the West. It would be interesting to see if @Dan Wich can find a lab provider that can do such a test. I would also be curious to hear what @Travis thinks the role of L-lysine oxidase is in the inhibition of metastases is (and lowering of the polyamine ratio). I am not aware of it being a direct factor in the metabolism of polyamines. Maybe by metabolizing lysine it affects the availability of arginine/ornithine and thus polyamine synthesis?? One possible benefit of lysine oxidase would be the reductions in lysine availability, which may limit the activity of the enzyme ornithine decarboxylase (which synthesizes putrescine).
Ornithine decarboxylase - Wikipedia
"...Lysine 69 on ornithine decarboxylase (ODC) binds the cofactor pyridoxal phosphate to form a Schiff base. Ornithine displaces the lysine to form a Schiff base attached to ODC, which decarboxylates to form a quinoidintermediate. This intermediate rearranges to form a Schiff base attached to putrescine, which is attacked by lysine to release putrescine product and reform PLP-bound ODC."

Interestingly, synthetic versions of spermine (closely related to spermidine), which when administered would lower the putrescine/spermidine ratio, has been studied in the past as treatment of advanced forms of cancer.
Spermine - Wikipedia
"...A derivative of spermine, N1, N12-bis(ethyl)spermine (also known as BESm) was investigated in the late 1980s along with similar polyamine analogues for its potential as a cancer therapy.[8][9]"

Anyways, it looks like digestion is one again implicated in the development and progression of cancer as putrescine and cadaverine are synthesized primarily in the gut, from undigested food.

https://link.springer.com/article/10.1007/BF00841381
Antimetastatic effect of L-lysine- α-oxidase
[Antimetastatic effect of L-lysine-alpha oxidase]. - PubMed - NCBI
"...On the other hand, a polyamine test (determination of the polyamine level in erythrocytes, blood serum, and urine) is widely used in clinical oncology to determine both activity of the tumor process and the effectiveness of treatment of cancer patients [2, 13]. Previously the writers found that the enzyme L-lysine-a-oxidase (LO), isolated from Trichoderma harzianum Rifai, possesses an antitumor action [7, 8]."

"...The antimetastatic effect of LO, injected in different concentrations (Table 1), was studied. Reduction of the volume and number of metastases of Lewis carcinoma in mice was observed after injection of the preparation in a dose of 10 IU/kg, whereas the maximal antimetastatic action was observed when the enzyme was used in a dose of 50 IU/kg. As Table 2 shows, surgical removal of the primary tumor (on the 15th day after transplantation) led to a sharp increase in the volume and number of metastases in the lungs compared with intact animals. The possible cause of this phenomenon, according to several investigators, may be stressor reactions arising in the host after resection of the tumor [1]. When the enzyme was injected into mice in a concentration of 50 IU/kg the number of metastases in the lungs was reduced by 3.6 times and their volume was reduced by 10 times compared with values obtained in animals not receiving the preparation."

"...Moreover, on the 15th day after injection of the tumor cells a decrease in the putrescine concentration and an increase in the molar ratio of putrescine/spermidine was observed in the erythrocytes of mice receiving the preparation compared with the group of untreated mice (Table 3). Since the putrescine concentration and the putrescine/spermidine ratio in the erythrocytes (or in blood serum) reflects the rate of proliferation of tumor cells of any kind [13], our results showing a decrease in these parameters can most probably be taken as evidence of the cytostatic action of LO. On the 30th day the polyamine concentrations in the erythrocytes were lower than on the 15th day, possibly due to the absence of the primary tumor. The spermine and spermidine levels in the two groups of mice studied on the 30th day did not differ significantly. However, the putrescine concentration and the putrescine/spermidine ratio were considerably less in the erythrocytes of the mice receiving LO than in animals not receiving the preparation, and this was probably due to reduction of activity of the metastasization process as a result of injection of the enzyme preparation."
 
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Wagner83

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Would a vegetarian diet with digestible foods and perhaps some cascara be therapeutic?
 
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haidut

haidut

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Would a vegetarian diet with digestible foods and perhaps some cascara be therapeutic and wouldn't it be close to Koch's treatment for cancer?

I don't think a vegetarian diet would be better than another one, as putrescine is formed from ornithine (which is itself formed from arginine) and this amino acid can be obtained on any diet. However, arginine depletion would likely help (as it has been shown in many studies) by limiting the source of raw material for ornithine and thus putrescine. Of course, the reduction in NO synthesis from lower arginine availability is also very therapeutic, and Peat has spoken many times about that.
So, avoiding protein high in arginine would probably be the most relevant dietary restriction.
 

Wagner83

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I don't think a vegetarian diet would be better than another one, as putrescine is formed from ornithine (which is itself formed from arginine) and this amino acid can be obtained on any diet. However, arginine depletion would likely help (as it has been shown in many studies) by limiting the source of raw material for ornithine and thus putrescine. Of course, the reduction in NO synthesis from lower arginine availability is also very therapeutic, and Peat has spoken many times about that.
So, avoiding protein high in arginine would probably be the most relevant dietary restriction.

Ok but what about cadaverine? Isn't it made exclusively from meat and fish?
 
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haidut

haidut

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Ok but what about cadaverine? Isn't it made exclusively from meat and fish?

Nope, cadaverine is derived from lysine, which is present in nearly all complete protein. So, avoiding animal protein will not do much good. I think the only reason for avoiding animal protein is that it is harder to digest than some other proteins but its NNU seems to be higher than legumes and grains, so it meat still seems better overall.
 

Travis

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I don't think cadaverine is dangerous. While true that it's listed among the polyamines, this is not even technically true. Both cadaverine and putrescine are diamines, and not yet polymers of diamines. Spermidine and spermine are polyamines, yet both are made from one putrescine and either one or two methionines. The diamine cadaverine, from lysine, never even enters the picture. In all aspects—such as PCR replication rates and microtubule stabilization—spermine is found to be the 'active polyamine,' with the shorter spermidine less active and putrescine basically inert. However: putrescine can be seen as proto‐spermine, and can be seen as a risk factor for that reason.

If anyone has evidence that cadaverine, from lysine, can actually form a polyamine I'd like to see it.
 
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Travis

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Williams-Ashman, H. G. "Methylglyoxal bis‐guanylhydrazone as a potent inhibitor of mammalian and yeast S-adenosylmethionine decarboxylases." Biochemical and biophysical research communications (1972)

One of the first studies on the classic polyamine inhibitor methylglyoxal bis‐guanylhydrazone. Notable is that S‐adenosylmethionine decarboxylase activity is increased with decreasing pH, and there is some indication that cadaverine could become an active polyamine. For that, I found this study:

Alhonen-Hongisto, L. "Replacement of natural polyamines by cadaverine and its aminopropyl derivatives in Ehrlich ascites carcinoma cells." Biochemical and biophysical research communications (1982)

It appears as though cadaverine can indeed substitute for putrescine, forming unconventional polyamines:

'The natural polyamines putrescine, spermidine and spermine are apparently required for normal cell proliferation as an inhibition of their accumulation in animal cells leads to a more or less complete cease of cell division (for ref. see 1). In some cases the requirements for the natural polyamines can apparently be largely fulfilled by closely related amines such as 1,3‐diaminopropane or cadaverine at least for short periods of time (2,3).' ―Alhonen-Hongisto

'Cadaverine, acts as a substrate for spermidine synthase though at a rate of only 3 to 10% of that of putrescine (4,5), and is converted to N‐(3‐aminopropylcadaverine and N,N'‐bis(3‐aminopropyl)cadaverine in Ehrlich ascites carcinoma cells exposed to GFMO (6).' ―Alhonen-Hongisto

'...we have succeeded to replace the natural polyamines by cadaverine-derived amines to an extent that no putrescine or spermidine and only traces of spermine remained. The new polyamine pattern appeared to be compatible with life, since these cells continued to grow, albeit slowly, for several months, yet they continued to express changes that are typical to polyamine depleted cells.' ―Alhonen-Hongisto

polyamine.png
Image fully embiggened

'The induction of adenosylmethionine decarboxylase by polyamine depletion is a well documented phenomenon (2,17,18,20), as is the striking enhancement of polyamine/MGBG [methylglyoxal bis‐guanylhydrazone] transport in response to DFMO [difluoromethylornithine] (19,20). As shown here, both these compensatory mechanisms remained operating in spite of high intracellular concentrations of cadaverine and N‐(3‐aminopropyl)‐cadaverine [cadaverine's spermidine analogue].' ―Alhonen-Hongisto

Despite the replacement of the natural polyamines by their cadaverine analogues, these cells still acted like polyamine‐depleted cells; they strongly upregulated (~10×) the enzymes ornithine decarboxylase and SAM decarboxylase, and also decreased arginase—the enzyme which creates ornithine from arginine, and also forming urea with the other part.. .

So this is most likely why lysine isn't a real powerful inducer of growth like methionine is. Lysine can form two polyamines—called N‐(3‐aminopropyl)‐cadaverine and N,N'-bis-(3-aminopropyl)cadaverine—perfectly analogous to the normal ones but having one less carbon; yet these are not nearly as effective as the natural polyamines derived from ornithine at inducing proliferation.

Because N,N'-bis-(3-aminopropyl)cadaverine is such a long name, we do need a shorter one. I think perhaps we should call it effeminine, due to its inability to increase growth.
 
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Travis

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Spermidine is a positive thing to eat, have I got that right? Mushrooms seem a good "Peat" source.
This is a persistent myth in San Fransisco, but I think consuming spermidine should probably be avoided—whatever the source.
 

Wagner83

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https://www.sciencedaily.com/releases/2017/04/170421091816.htm

April 21, 2017, Texas A&M University

Summary:
Spermidine—a compound found in foods like aged cheese, mushrooms, soy products, legumes, corn and whole grains—seems to prevent (at least in animal models) liver fibrosis and hepatocellular carcinoma, which is the most common type of liver cancer.

Spermidine -- a compound found in foods like aged cheese, mushrooms, soy products, legumes, corn and whole grains -- seems to prevent (at least in animal models) liver fibrosis and hepatocellular carcinoma, which is the most common type of liver cancer. There is also some evidence that it may prolong lifespan, according to a study published recently in the journal Cancer Research.

This is a persistent myth in San Fransisco, but I think consuming spermidine should probably be avoided—whatever the source.
:rolling
 

Wagner83

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Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy
Here is the study, I think like he said previously in the thread, spermidine is a polyamine. Universal Test For Cancer Progression/stage
Btw if spermine and spermidine were first discovered in semen, doesn't it mean that not ejaculating often enough could be bad for the prostate or health in general (build up of polyamines) ? There was a study which showed men who ejaculated (if I remember right:) once a week had less chances of developping prostate cancer.
 

raypeatclips

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Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy
Here is the study, I think like he said previously in the thread, spermidine is a polyamine. Universal Test For Cancer Progression/stage
Btw if spermine and spermidine were first discovered in semen, doesn't it mean that not ejaculating often enough could be bad for the prostate or health in general (build up of polyamines) ? There was a study which showed men who ejaculated (if I remember right:) once a week had less chances of developping prostate cancer.

I saw that post from him but then the study you posted made me think it was a positive thing, and haiduts first post suggested spermine as a potential cancer treatment.
 

Nighteyes

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Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy
Here is the study, I think like he said previously in the thread, spermidine is a polyamine. Universal Test For Cancer Progression/stage
Btw if spermine and spermidine were first discovered in semen, doesn't it mean that not ejaculating often enough could be bad for the prostate or health in general (build up of polyamines) ? There was a study which showed men who ejaculated (if I remember right:) once a week had less chances of developping prostate cancer.

I asked Peat about this a while back:

Dear Dr. Peat
Do you think abstinence as a male could potentially lead to accumulation of polyamines such as putresine and spermine? These are suppressive of metabolism are they not?
Regards

"I think its effect would be mostly in the prostate."
Biosci Rep. 2017 Jul 12;37(4). pii: BSR20170163.

Characterization of an androgen-responsive, ornithine decarboxylase-related
protein in mouse kidney.
Silander KM(1), Pihlajamaa P(2), Sahu B(2), Jänne OA(3), Andersson LC(4).
(1)Department of Pathology, Haartman Institute, University of Helsinki, Helsinki,
Finland [email protected].

(2)Genome-Scale Biology Program, Research Programs Unit, Biomedicum Helsinki,
University of Helsinki, Helsinki, Finland.
(3)Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of
Helsinki, Helsinki, Finland.
(4)Department of Pathology, Haartman Institute, University of Helsinki, Helsinki,
Finland.
We have investigated and characterized a novel ornithine decarboxylase (ODC)
related protein (ODCrp) also annotated as gm853. ODCrp shows 41% amino acid
sequence identity with ODC and 38% with ODC antizyme inhibitor 1 (AZIN1). The
Odcrp gene is selectively expressed in the epithelium of proximal tubuli of mouse
kidney with higher expression in males than in females. Like Odc in mouse kidney,
Odcrp is also androgen responsive with androgen receptor (AR)-binding loci within
its regulatory region. ODCrp forms homodimers but does not heterodimerize with
ODC. Although ODCrp contains 20 amino acid residues known to be necessary for the
catalytic activity of ODC, no decarboxylase activity could be found with
ornithine, lysine or arginine as substrates. ODCrp does not function as an AZIN,
as it neither binds ODC antizyme 1 (OAZ1) nor prevents OAZ-mediated inactivation
and degradation of ODC. ODCrp itself is degraded via ubiquination and mutation of
Cys(363) (corresponding to Cys(360) of ODC) appears to destabilize the protein.
Evidence for a function of ODCrp was found in ODC assays on lysates from
transfected Cos-7 cells where ODCrp repressed the activity of endogenous ODC
while Cys(363)Ala mutated ODCrp increased the enzymatic activity of endogenous
ODC.


2. Am J Pathol. 2016 Dec;186(12):3131-3145.
Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen
Receptor Signaling.
Shukla-Dave A(1), Castillo-Martin M(2), Chen M(3), Lobo J(4), Gladoun N(5),
Collazo-Lorduy A(6), Khan FM(5), Ponomarev V(4), Yi Z(7), Zhang W(7), Pandolfi
PP(3), Hricak H(4), Cordon-Cardo C(8).
(1)Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New
York, New York; Department of Radiology, Memorial Sloan Kettering Cancer Center,
New York, New York.
(2)Department of Pathology, Icahn School of Medicine at Mount Sinai, New York,
New York; Department of Pathology, Champalimaud Centre for the Unknown, Lisbon,
Portugal.
(3)Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts.
(4)Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New

York.

(5)Department of Pathology, Icahn School of Medicine at Mount Sinai, New York,
New York.
(6)Department of Pathology, Icahn School of Medicine at Mount Sinai, New York,
New York; Spanish Society of Medical Oncology, Madrid, Spain.
(7)Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New
York.

(8)Department of Pathology, Icahn School of Medicine at Mount Sinai, New York,
New York. Electronic address: [email protected].
Increased polyamine synthesis is known to play an important role in prostate
cancer. We aimed to explore its functional significance in prostate tumor
initiation and its link to androgen receptor (AR) signaling. For this purpose, we
generated a new cell line derived from normal epithelial prostate cells (RWPE-1)
with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and
in vivo experiments. We then comprehensively analyzed the expression of the main
metabolic enzymes of the polyamine pathway and spermine abundance in 120
well-characterized cases of human prostate cancer and high-grade prostate
intraepithelial neoplasia (HGPIN). Herein, we show that the ODC-overexpressing
prostate cells underwent malignant transformation, revealing that ODC is
sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic
capacity was acquired through alteration of critical signaling networks,
including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the line
between AR signaling and polyamine metabolism. Human prostate cancers
consistently demonstrated up-regulation of the main polyamine enzymes analyzed
(ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This
phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant
transformation. In summary, we report that ODC plays a key role in prostate
tumorigenesis and that the polyamine pathway is altered as early as HGPIN.



J Pharmacol Exp Ther. 2001 Feb;296(2):372-7.
Regulation of ornithine decarboxylase activity and polyamine transport by
agmatine in rat pulmonary artery endothelial cells.
Babál P(1), Ruchko M, Campbell CC, Gilmour SP, Mitchell JL, Olson JW, Gillespie
MN.

(1)Department of Pathology, Comenius University, Bratislava, Slovakia.
Agmatine, a product of arginine decarboxylation in mammalian cells, is believed
to govern cell polyamines by inducing antizyme, which in turn suppresses
ornithine decarboxylase (ODC) activity and polyamine uptake. However, since
agmatine is structurally similar to the polyamines, it is possible that it exerts
antizyme-independent actions on polyamine regulatory pathways. The present study
determined whether agmatine inhibited ODC activity and polyamine transport in rat
pulmonary artery endothelial cells (PAECs) by an antizyme-dependent mechanism.
Agmatine caused time-dependent reductions in ODC activity, which occurred before
increases in antizyme. Interventions that suppressed proteasome function caused
large increases in ODC activity but failed to attenuate inhibitory effects of
agmatine. When agmatine was present in the culture medium, 14C-polyamine uptake
was competitively inhibited as evidenced by substantial elevations in K(m)
values. If PAECs were incubated with agmatine for periods sufficient to increase
antizyme, there were modest decreases in V(max) for putrescine and spermidine but
not for spermine. These effects of agmatine on polyamine transport were
insensitive to protein synthesis inhibition. Collectively, our findings show that
agmatine decreases ODC activity and polyamine transport in PAECs, but a causal
role for antizyme in these actions of agmatine is difficult to establish.
Nevertheless, these observations are consistent with a model in which PAECs
express both antizyme-1 and -2, but only the latter contributes to
agmatine-mediated suppression of ODC activity.
 

Travis

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I was being facetious. Although polyamines inside of cells powerfully increase proliferation, polyamines outside of the cells don't have as much effect. Besides having dedicated enzymes such as polyamine oxidase, excessive polyamines can also be degraded by the ubiquitous monoamine oxidase. The soy bean, despite having an unusaully high amount of polyamines, isn't particularly correlated with colon cancer. So perhaps dietary polyamines—whatever their source (wink)—shouldn't automatically be considered carcinogenic.

Suppose those things Bruce and Lance told us in The Navy were actually true?

Perhaps counterintuitively—after considering these catabolic enzymes—a better way to get polyamines inside of the cell seems to be by ingesting their precursors, methionine and ornithine, and not the polyamines themselves. A similar thing can be said about methylgloxal whose high reactivity prohibits direct use, intracellular levels of which are best increased through the ingestion of L‐threonine and glyoxylase I inhibitors—not oral ingestion.
 

Obi-wan

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I try to take a little baking soda and water every night as I feel it really helps in digestion. No waking up in the middle of the night with heartburn. Could this help in decaying food in the gut?
 
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