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Advanced Prostate Cancer
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PCA Cells Lacking PTEN Are Vulnerable To Drugs That Impair Mitochondria Function

Scientists have discovered that cells lacking the tumor suppressor Gene PTEN--->a feature of many cancers, including Pca----> are particularly vulnerable to drugs that impair their energy producing mitochondria. Such drugs induce these cancer cells to eat themselves to death in search of food for energy.

Unlike normal cells, cells without PTEN seem driven to preserve their mitochondria, at all costs, says a Team Leader of a research laboratory group. The researchers found that when such cells are treated with certain mitochondria inhibitors, they consume vast quantities of glucose to fuel their efforts. As a result they run out of energy quickly, and die.

Metformin, a widely prescribed drug for diabetes, acts as a mitochondria inhibitor. How efficiently, as to action on the mitochondria has not been well investigated. New findings reported in 'Cell Reports', that drugs like Metformin have the potential to eliminate cancer cells at doses that leave healthy cells intact. The timing of Metformin, Et. Al. is critical. When glucose levels are high, the window of use is lost. Indicating that we may be taking Metformin after meals when glucose levels are high, and it may be beneficial to take these drugs when the glucose levels are low.

Two related compounds, both derived from the root of the same plant, were screened. Both compounds killed cells missing PTEN and another tumor suppressor, p53. Loss of these together is common among men with advanced prostate cancer and is associated with highly metastatic disease. I understand those of us with these losses do not want to hear this, but, it is true. The 2 drugs were found to have little effect on cells having functional PTEN. But the drugs Rotenone and Deguelin, are found to be viable mitochondria inhibitors.

Interesting, experiments found that these drugs would shut down mitochondria in cells with PTEN, as it does with cells without. This is IMPORTANT---> why did cells with PTEN tolerate the toxic compounds, while those without did not?

The answer seems to be how cells use glucose. Researchers found that cells without [PTEN], I.E. Pca cells, use glucose from their environment to generate the energy rich molecule--->ATP, which they import into mitochondria to keep them intact. This is the complete opposite of what mitochondria are suppose to be doing. Mitochondria are suppose to generate ATP for the rest of the cell. For these cells lacking PTEN, unless there is an endless supply of glucose, they quickly use up the sugar and die.

The researchers postulate that eventually, any cell subjected to mitochondria inhibitors will run out of energy and die. Cells without PTEN, just get to die faster. Thus as indicated with Metformin, it would be best to administer these drugs when the blood sugar of the patient is low. As Metformin, and Berberine are indicated to take after meals. This research, may suggest pharmacologists relook the use of Metformin use, especially after what the researchers found with Rotenone and Deguelin.

For the Naturalist here, both drugs are isoflavones, found in the stems vines, and seeds, of the Jicana Root Vegetable, widely grown in Mexico and Central America. In scientific terminology, these compounds block an enzyme [NADH Ubiquinone Reductase], which prevents availability of oxygen for cellular respiration---thus the blocking of the Cells lacking PTEN, from getting Glucose.

Of special note these compounds are not new. They have been used for decades as natural commercial Pesticides, and Insecticides. Its killing action, may be similar to killing cancer cells. No longer approved for its commercial use, due to its poisonous capabilities, yet so are our Chemo Drugs poisons, and when used in correct controlled ways, can kill cancer cells.

Nalakrats.

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Thanks for the post....Talking to my MO about adding metformin to my Zytiga/Lupron regimen...praying they are doing their job...

Fish

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I added Metformin a few months ago....to Xtandi and Lupron...however, I accidentally took it on an empty stomach a couple of times (as the article suggests is better, If I'm reading it correctly) and I felt TERRIBLE...like my stomach was going to lurch out of me....cramps and nausea bad. As long as I do it after a hearty breakfast...there's not problem. I haven't seen remarkable results(yet) on PSA ...but always optimistic that it's one of several things I do which might help.

John

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We all take with food, yet there is a Metformin that is Time released, that might do better with an empty stomach. I have both, I am going to try dividing regular with food and Extended release between meals.

Nalakrats

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how much do you take? I only have a prescription for one daily. (500 mg)

should I ask for more? I had to get these through my primary care doctor...the oncologist would NOT prescribe.

John

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I cannot prescribe as you know. I can tell you I use both Extended and regular Metformin Daily. And like others here our use levels approach or are 2,000 Mgs a day. I suggest you talk to your provider. You can print off papers from Google---Metformin and Prostate Cancer, to support a position.

Nalakrats

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thanks, I'll work on it on my next visit....and hope she goes along.

John

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The preferred dose is 2,000 mg, in a divided dose, but one should work slowly up to that dose.

-Patrick

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I'll have to see if my primary care doctor will up the dosage that much. I guess I ask for 2

/500mg a day and try that for 3 month...then go for 4/ 500 mg dosage...if she'll do it.

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Hoping an important point in my post was understood, as we are told to take Metformin with Food, and it might be better to take when our blood sugar is low, for best results.

Nalakrats

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when I accidentally took it on an empty stomach...I was ready to go to the emergency room...my stomach felt really bad...like it was trying to escape out of me! I don't know if I could tolerate it...I ran an researched the drug and realized what I had done and ate a high fat quick meal and started feeling better in about 20 minutes.

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GJ,

try Berberine just as good as Metformin and easier on the stomach

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gus, do you know how much Berberine is equal to 1000 mg Metformin?

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I eat some sardines or similar before if necessary

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So we need to eat something that has a very low glycemic index [GI]? Mushrooms are 15, as are olives & broccoli. Avocado is 10. Fat delays the appearance of glucose in the blood.

-Patrick

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Yeah, Patrick, a good plan I guess. But this work by Cold Harbor Labs, is indicating a better benefit from Metformin, when our blood sugar is low at the time of the day we take it. If there is indigestion, or stomach stress on an empty stomach, taking Metformin with a low GI food like Avocado, or a favorite of mine steamed Broccoli, and some butter/salt, might be the way to go. Anyway the Isoflavones I mentioned are strong Mitochondria inhibitors, stronger than Metformin. Since they were approved Insecticides at one time, they are probably not considered GRAS, and we could probably get all we want in Mexico. The Lab doing the research, are not indicating dose preferences, by body weight. But we get a better understanding of the action of Metformin, thru their work.

Nalakrats

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Did you mean Jicama (Hick ah ma)? Does the root of the vegetable have anti cancer properties or is it the poison in the stems and leaves that kill cancer cells? I'd love to hear more about it when you have the time.

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Yes I did--sorry about my spelling--the n and m key are next to each other. Thanks for catching it.

Nalakrats

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Its the roots and stems. But I would not eat them, as these are powerful Natural Isoflavones. I.E. the stems of tomatoes are poisonous to humans. but these Isoflavones can be bought in crystalline form on the open market. I may list where one can buy them.

Nalakrats

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What I wrote is the gist of it---these compounds can be bought pure overseas, using the Alibaba Site. Cost is about 50 dollars per kilogram. Enough to treat a 1,000 men for a year I would think. I would think a few milligrams per dose would be a starting point. But I am not about to try. The cheap cost of these insecticides, will never allow for a Phase Trial Test. Big Pharma, you know?????

Nalakrats

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My blood panel shows no risk for Metformin, in fact, can use the possible weight loss benefits as well.

Mainstream oncologist docs just don't like to prescribe it. I'm reluctant to use Care Oncology just to get it.

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The drug is older than some of the Docs. you see---what is their problem? Stupidity? I would stand on their desk and start throwing research paper after paper, that have been peer reviewed until the Doctor relented. If that does not work you might do what I do fire him/her. I have fired 4 doctors since 2011. I am thinking of getting rid of another this 1st quarter of the year. If he opens his mouth about Standard Of Care, and that I do not Follow it, one more time--he is gone.

Nalakrats

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Actually, I just did switched to Dana-Farber (DFCI) from Lahey Health Systems (LHS), Hematology Oncologist. The LHS doc sees all cancer patients, strictly PCa Standard of Care compliant. I've Dx init at 09/11/2018, so ramping up.

Anyway, now my lead DFCI doc is Mark Pomerantz, folks the difference is amazing, in just a few months of learning and research, I've overwhelmed my LHS oncologist doc.

Will ask for Metformin with Mark next visit, my current concern was the hot flashes, disrupting my sleep and focus on work.

FYI: The DFCI team prescribed Venlafaxine for hot flashes relief, the drug is mainly for depression and anxiety, but it has shown beneficial for depressing hot flashes. Although, will admit, I'm an obnoxious mental thinker, so let's see if the drug turns a single into a double...

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Good Luck, on the double.

Nalakrats

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Primary care general practice practitioners should have no problem with prescribing 2000mg metformin. It makes sense for people in our situation to keep insulin and blood sugars under control. It should be part of our general treatment plan. In addition, any sign of a pre diabetic condition, glucose intolerance etc, is a good excuse for metformin. Apart from its specific effects on PCa. My onc said it was widely believed that it has a benefit but nobody had found out why and how. I guess we are starting to find out.

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My post shows how it probably works based on the work with the 2 Isoflavones that were discussed in my post.

Nalakrats

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My GP doctor refused my request for a metformin prescription. I forgot to ask my urologist about it the last time I saw him. I suppose I could just take berberine on my own. I am taking Bitter Melon Fruit supplement.

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Many feel you can get the same affect with Berberine---but I would research, the relationship, between the use levels of the 2. Probably you can Google Berberine and Metformin and their comparison. Your Doctor is an IDIOT.

Nalakrats

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Standard of care. POS. I hate that term. I had to pay large for appropriate treatment, with curative intent.

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I hate it worse, it is completely opposite of ingenuity-----> being able to think outside the box.

Nalakrats

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I was reading up on Rotenone says being tested for anti-cancer but has also been implicated in causing Parkinson's disease. Below is a pic of Nalakrats who has been on Rotenone for 3 days. It actually scared off a Gator that had been tracking him.

Gus

images.buzzerie.com/2013/09...

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Thanks for posting this! Just yesterday I provided a saliva sample for genetic testing. They will be looking at 83 gene variants (not as comprehensive as Foundation One, but it's a start). Anyway, PTEN is one of the 83 they will be testing for. Thank you!

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Always:

Nalakrats

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Thanks for the great post Nalakrats. I'm still trying to get a prescription for Metformin. It's not easy. My MO wasn't interested at all and my GP was dubious. So my wife put together a 'case' for him to read which included several papers on trials and studies. We await his response. In the meantime we're organising to see another MO who hopefully will be more amenable. Maybe it's harder to get a Metformin prescription in Australia than in the US if you're not yet diabetic. Any in OZ managed it?

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Good for your wife--I mean this is not radical--it is not even thinking outside of the box, in some Clinical Centers of Excellence, it is becoming almost a Standard of Care, i the USA--but not quite--I said almost. Get those Aussie Docs. up to speed. Sometimes the patient has to be the teacher.

Nalakrats

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Until you get your Metformin script, consider Berberine root, its bio-equivalent. It is sold OTC, and online you can find a number of distributors handling berberine. I take 4 capsules at every meal. It really knocked down my A1c level from pre-diabetic to normal. My PCP was quite pleased.

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Thanks CalBear74. I’ve read a bit about this. Can I ask what brand and what dose the pills are?

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I use Solaray Berberine 500 mg. I take 4 as I said, so that is 2,000 mg 3x daily.

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Thanks!

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Great and very relevant post

Dr Myers put me on soy isoflavones and resveratrol to try to deal with PTEN hypermythelation , as well as 2000mg metformin

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What was the concoction of Soy Isoflavones called>

Nalakrats

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Life extension

Super absorbable soy isoflavones

Novasoy 135mg standardized to 40pct 54mg

Genistein and precursor 28mg

Daidzein and precursor 22 mg

Glycitein and precursor 4 mg

Soynatto fermented soyfood 435mg

I take per his instructions, 2 pills x 2 day

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Since Genistein is the main key component, and the one tested solo in trial phase testing, why not use just Genistein and not ingest the NattoSoy. Some of us including me like to keep all soy out of the diet, but pure Genistein, has no soy components, such as Swanson's non soy Genistein, I believe one capsule has 125 Mgs of Genistein.

Nalakrats

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Do you take this as well once or twice a day?

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Twice a day, with water, as the label says how to take.

Nalakrats

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I've been taking roughly 35 different supplements daily for at least the last couple of years and as I don't do soy, I added two of these daily six months ago. I went for my 3 month Lupron shot that I get every four months at the beginning of January and received some surprising news. My testosterone had reached undetectable and my bloodwork and liver enzymes were excellent. However my psa had gone from 0.5 in September to 15 in December and to the low twenties beginning of January. My Doc switched my Preds to Dexa and ordered some scans, believing that my 18 months on Zytiga was running out.

I'm not willing to accept this theory and two variables that came into play are the addition of this supplement and letting my diet and complementary therapies lapse for the summer, which continued up to the end of the year. No red meat, dairy or alcohol, but I ate a lot of crap nonetheless, believing the supplements would negate any harm caused by not adhering to my strict anticancer protocols.

So I've shelved this supplement while I get back in the saddle and work to bring my psa down to the 0.5 mark. When I search Genistein, I get dozens of pages singing the praises of it being protective but there are also a few studies that explain how it may harm hormone sensitive cells but cause castrate resistant cells to proliferate.

Patrick wrote about this in another post and brought up the biphasic effect of Genistein, which makes me wonder about the dosage required to cross the threshold. For me, two may not have been enough but three or four may have provided a different result. Of course, there is no evidence to suggest that this supplement had anything to do with my rising psa, but I cannot continue to take it until I get my psa back down and am convinced that it would benefit and not cause harm.

And when I do reach my nadir again, I'm sure the Dexa will get all the glory and everything I've done will be discarded as irrelevant. I'll update my progress as I learn more and look forward to your continued research on this supplement.

ncbi.nlm.nih.gov/pmc/articl...

healthunlocked.com/advanced...

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thanks

I assume you checked out the Swanson quality control

how much of the Swanson non soy would be a safe maximum

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A researcher who buys his on Amazon, a PHD/MD checked it out for his PCA, and posted on Amazon. I myself have not yet done any work on it, as it is new to my supplemental library. When I have a rainy day--I will be in touch with Swanson's QC.

Nalakrats

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Thanks

Pls let know what u find out

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My concern overall, is that the Genistein, is still a Estrogen type Molecule. And some of the work done by Patrick 2 years ago, threw some mud in the water about use levels---where not enough of the Genistein might be harmful where a lot in the use level may be beneficial--the Swanson People do not collect research data on Pca patients, so they cannot offer clinical advice. Now I understand the work Patrick did, was based on a complex in which Genistein was just one of a few compounds. And Genistein, should stand alone, as being a mono molecule therapy.

So I have not gained enough info, to personally want to upset my balance. As my theories, are in line with Dr. Friedman's and to use 5-A-R, and anti-Aromatase molecules/drugs to keep anything estrogen like away from the Pca cells, even if Dormant. So I will not use for now.

Nalakrats

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Well shoot, I feel like such a newbie to so much of the information shared in this group. This topic of Metformin in conjunction with HT is new to me!

I read a few articles that explained that when added to hormone therapy Metformin increases OS and slows progression, not to mention the other “on label” benefits.

So I think my dad would be a perfect candidate for this. He’s been on hormone therapy for 3 1/2 years now. His last PSA test showed that it is holding steady at .07. However, some of his standard panels are starting to get a little wonky from the therapy. His LDL cholesterol and glucose were both elevated. Nothing out of this world, but enough that we might have a case for adding Metformin.

Can anyone share with me their experience with the drug? I’m concerned about side effects. My dad is very skeptical about adding in additional prescription drugs and tries his hardest to go a more holistic way. If I can assure him that the medicine doesn’t come along with a lot of side effects and that the benefits outweigh any risk for side effects, I might have a case with him and his oncologist!

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Is your dad on a statin drug to manage the LDL. The medical director of our medical software company stressed that I should never allow my LDL to exceed 100. His judgment was based on personal experience as a ER doc of many years and then a family practitioner. He also used the Framingham Heart Study to justify the 100 number. That was 20+ years ago and I started taking red yeast rice (Solaray brand) OTC. My LDL never gets over 80 taking 2,400 mg. in two divided doses daily.

I combine berberine root with red yeast daily to augment my supplement regimen.

Never had side effects with either one. I have been on berberine for more than 2 years.

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Thank you! I will certainly pocket these options, as I said, he’s very suspicious of pharmaceutical medicine! And no, he’s not on anything for cholesterol or for diabetes. Right now he’s getting Lupron every three months, taking Casodex daily and is also on blood pressure medicine. Unfortunately he has battled high BP for years! He tried managing it naturally, but despite his best efforts it wouldn’t respond!

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I am also in a constant battle with my BP. At first I tried natural remedies, but they did not work. I now use several prescription medications.

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What have you tried Naturally--I am sure you have not tried my concoction.

Nalakrats

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I have 3 years with it, with Undetectable PSA, I am just one. There are no side effects, that I can determine. We have hundreds of men doing the Metformin Addition to their protocol.

The benefit of lowering the Blood Sugar, which always goes up on HT, is a positive to the entire body. And many studies indicate that keeping your Blood Sugar down, helps in weight control, and gives less fuel to the cancer cells.

Nalakrats

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Thank you for sharing your experience! I’m always trying to find the balance between his health and quality-of-life. And given his general suspicion to pharmaceutical drugs, it always helps my case if I can say that I researched a bit and found that the side effects were generally tolerable!

Looking at his lab reports, his fasting glucose levels were 115, his chloride was slightly elevated (106) and his LDL cholesterol was 115. All of his other levels were good. He is trying to implement more lifestyle changes. He has been exercising for 30 minutes a day. He already eats a very clean diet so there isn’t much to change in that respect!

I am going to keep doing some research and pray about it. We have an appointment with his oncologist on Friday. If we don’t get snowed out up here in Ohio, I plan on bringing it up to him at the appointment! Thank you for your help in this matter!

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Nal, I heard somewhere that metformin use can make you feel weaker at the gym. If you use it I guess that can't be true?

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I see no difference. Unless you take enough that causes low blood sugar.

Nalakrats

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I have taken Metformin for many years with no discernible side effects. When I showed my Primary Care doc an early research

paper about PC he upped the dose

for me to 2000 mg a day. My MO was neutral. Everyone who is on Zytiga takes prednisone...since that messes up blood sugar levels, Metformin might be helpful.

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Nal,

I would appreciate if these excellent reports of yours would conclude with a brief summary listing of action steps recommended from your insights. For example, I would extract from what you have said that we who take either Metformin or berberine need to do so after our 3 meals a day. Would it be better to wait an hour or two until our glucose spike from eating has declined further?

The paragraph that begins "Two related compounds..." offers some interesting observations but I am apparently too dimwitted to understand fully what is going on. For example, what does this mean: why " those of us with these losses", etc... I don't know if I am in this group and not wanting to hear this. Please amplify this discussion, it seems important and if there is some actionable implication spell it out.

Sorry if I seem nitpicky; I taught college writing after retiring from the medical software world. I learned how to torment aspiring writers, particularly those writing on science topics.

Thanks Nal for all the time you put into preparing this document. This is a very important ministry of yours. I personally greatly appreciate it.

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Sorry I replied to you with about 8 paragraphs and when I clicked on reply it went poof.

To busy to rewrite--and you know I am on vacation---seems I lost the Internet connection for an instant.

Nalakrats

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Going to try again with my morning coffee! Thanks for recognizing that what I do is a ministry. As it truly is!

My insight as to the best time to take Metformin, from the research summary, is when the blood sugar is low. This was an extrapolation on how best the 2 pesticides worked to kill Pca cells. The pesticides worked better when the blood sugar was low, in terms of kill rate of Pca cells. The researchers later in their work, indicated that Metformin which probably works the same way as the pesticides, might also work better during times of the day when the blood sugar is low.

So our prescriptions say to take with food. But this is standard for diabetes! We have Pca! Yes we take Metformin to keep blood sugar low against the rising tide from our drug treatments, but the main reason is to interfere with the mitochondria of the Pca cells, so they kill themselves. So all you can get out of this is it might be better to take Metformin during the day or night, when you know your blood sugar is low--you can tell when you are hungry. So for example I took mine yesterday with a hand full of broccoli, later a slice of cheese, and a small amount of protein powder. I waited an hour than ate. This is just an extrapolation, form the work on Rotenone and Deguelin.

So as to losses, this is in reference to PTEN mutation loss in Pca cells. You obviously have not had yourself Gene Mapped. PTEN is a common defect in Men with Metastatic Pca. And we do not have yet direct targeted drugs to help this situation. Having the PTEN loss in the DNA of the Cancer cell, is usually down the road a death sentence. We have targeted drugs for BRCA 1, and 2, and a couple of others, but PTEN has been a hard problem to resolve.

The research, was directed at finding a way to kill Pca cells with PTEN loss. And on the way Metformin may act the same way as the pesticides.

I do not know what group you think you may be in or not. I am one with the PTEN mutation, and there are many other men here also. Many have been Gene Mapped, and know they have the PTEN loss or not. Metformin may be a help against this mutation, as the pesticides are not available for use as to treatment. I can buy these compounds, pure, overseas by the pound, but have no idea how to use. And would not attempt to.

What we learn is that if you interfere with the mitochondria of the Pca cell, by inhibiting them from getting glucose, they will eat themselves up seeking food for energy, which we call ATP.

So this research, gives us a roadmap, for further research.

On the way we found from other responders to my post the Genistein a compound found in Soy, may also work in the same way. This is how initial new research, expands the playing field.

I hope the above satisfies what you thought I needed to expand on. Off to going fishing!

Nalakrats

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Excellent. Thank you for the tutorial. I realize there are some changes I need to make in my daily routine.

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Would you happen to have a link to the original paper/discussion that this info was taken from so I can pass it along to my GP - asking him to double my dose? (Currently 500mg/daily - usually in the AM with my oatmeal and orange juice - may have to change that..)

Thanks!

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The information, of the paper was mostly addressing how to make the cancer cells run out of energy, by the use of mitochondria inhibitors, and the 2 new ones were Rotenone, and Deguelin, that are natural pesticides. The research, concluded, that it would be best to take any drugs that block Mitochondria when during the day your blood sugar was lowest to get the best effect, which then led to a discussion, that Metformin, works the same way, and we might consider taking, at another time of the day, as most prescriptions say to take with food. There was no recommendations of dosing. Metformin was an after thought to the research. But we that take it understand we need to get to 2,000 mgs per day.

Nalakrats

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Thanks. Where did the 2,000 mgs per day come from? Any "authority" on that or is it Internet "wisdom"?

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It is what pioneer Oncologists determined over a lot of years working with their patients. I am sure the makers of Metformin are happy to have a new use for their drug. This is not an internet thing. Further what was gleamed with their patients, the info was passed back and forth at Cancer Oncology seminars, and conferences, until dose levels and how to get there were determined.

Nalakrats

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OK. Thanks. I didn't doubt the value of Metformin - just wondering how the effective dose was arrived at - haven't found anything in the form of a study (yet..)

I *AM* taking Metformin - my med-onc in NYC (at Columbia University Med Center) told me a story - that was good to use with my GP.

I'm on Lupron. Lupron is known to screw up glucose levels. Metformin helps control them, hence - if someone is prescribed Lupron - it makes medical sense to also prescribe Metformin. He prescribed it without a problem.

The only trick is to get my GP to up the dose (double it to begin with, and see how my stomach likes it..) I imagine my blood sugar gets lowest during sleep - and possibly after exercise, so that gives me two target times to take a 500mg pill.

I'll have to email my GP.. I was hoping to provide him with an authoritative link. I'll just have to smooth talk him (we're pretty good friends - I have a bet going with him involving me walking into his office at age 80 - either way I win.. or lose depending on your point of view.)

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As I said this has been worked out, by oncologists over time--you may Google Prostate Cancer and what is the proper amount of Metformin to use. I know my Pharmacist does not know!

Nalakrats

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Great post. I read an article on the pesticides in Science Daily a couple of months ago that discussed this study. What is your source on that you got your info from? Trying to get our oncologist here to get my husband on Metformin but he is reluctant. As we live in a rather remote place with few options for docs is exceeding limited, switching is really not an option. Locally known as the paradise tax.

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Work was done if memory is correct by Cold Harbor Spring Labs. But their work was on the Pesticides. In passing they thought that since their pesticide work seemed to provide better results when the Blood Sugar was low, they suggested that the same might be true for the use of Metformin.

THEY DID NOT, advocate for the use of Metformin, just that those already taking it might want to not take it after a full meal when the blood sugar would be high, that better results might be observed if taking when blood sugar is low. They did no studies on Metformin!!

You can find other Peer Reviewed Papers to take to your Doctor.

Nalakrats

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Would in this case taking metformin during a 5 day fast be even better? Does berberine has the same action?

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Not sure if Berberine works the same way. But fasting or when sugar is low the research indicated getting better results, should occur with Metformin.

Nalakrats

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