Reversing the Warburg effect through Metabolic Modulation
When I realized that "Standard Therapy" wasn't going to do much for me, I started to research other options. I was starting to gain an understanding of how cancer metabolized and started looking for therapies that would interfere with that process. My tumor was highly estrogen and progesterone positive as well as having Her2/neu amplification. I was already on an aromatase inhibitor Anestrozole (the generic of Arimidex) an estrogen inhibitor, and to that I added Prolia (denosumab) which is an anti progesterone (anti-RANKL). The third task was to find something that would inhibit the Her2.
At that time the only thing I knew of that would do that job was Herceptin (trastuzumab) a monoclonal antibody that interferes with the HER2/neu receptor. The problem was that my oncologist at the time wouldn't give it to me straight, only as an adjuvant to Chemo and that wasn't going to happen. After I got rid of him and before I found a new oncologist. I found that there was a possible adjuvant that would help me. It was amazing to me at the time, but now that I understand tumor metabolics better I shouldn't have been surprised at all, that a cheap diabetic medication can inhibit the Her2 amplification in cancer. These are two diseases share the features of unmodulated insulin and problematic sugar metabolism.
Getting my new oncologist to prescribe it wasn't a big deal. The evidence for its use is overwhelming especially with its ability to destroy cancer stem cells (something that no cytotoxic chemotherapy has been shown to do) and the drug is very safe even for a non-diabetic. So the question is why isn't every cancer patient on this "Adjuvant"?
Metformin is an AMPK enhancer.
From Life Extension Magazine; November 2015, pg 12
AMPK (adenosine monophosphate-activated protein kinase) is in every cell of the body. It is sort of a metabolic master switch and controls many metabolic pathways that enable us to extract energy from food, as well as store and distribute that energy safely throughout the body. AMPK's job is to sense each cell's energy status. It inhibits tumor cell growth and promotes tumor cell destruction by apoptosis (programmed cell death). It increases cancer cell vulnerability to chemotherapy. And it switches cancer cells' metabolism from the unique ability to burn sugar in the absence of glucose toward a more normal oxygen-requiring pathway, thereby inhibiting tumor growth.
Numerous studies provide evidence of the anticancer effect of metformin. * A recent review published in PLOS One found an association between the diabetes medication and a significant reduction in the risk of colorectal, liver, pancreatic, stomach, and esophagus cancers in patients with myotonic dystrophy type II, an inherited disorder of the muscles and other body systems. A further study published in Cancer Prevention Research found that low doses of 250 mg per day of metformin administered for four weeks to nondiabetic patients suppressed markers for colorectal cancer.
Metformin may impact cancer through indirect (insulin-dependent) and/or direct (insulin-independent) mechanisms. Metformin reduced lung tumor development primarily through an insulin-dependent mechanism by decreasing circulating levels of insulin-like growth factor-I (IGF). IGF activates its receptor, which in addition to a metabolic effect promotes proliferation and metastasis. The direct-insulin independent antitumor action of metformin is mainly induced by activating the AMPK signaling pathway, resulting in an inhibition of the mammalian target of rapamycin (mTOR), a signaling pathway that plays a central role in cancer cell growth, proliferation, and pathogenesis.
The effects of metformin as a breast cancer target have been studied extensively. A study published in Cancer Research found that metformin targets cancer stem cell (tumor-initiating cells) in four genetically different kinds of breast cancer cell lines. Treatment with a low-dose of metformin was found to eliminate cancer stem cells, possibly due to the inhibition of the inflammatory pathway. This observation could be the definitive link between the diabetic drug and its anticancer benefits, since inflammation plays a key role in both diseases.
Editor's Note: Life Extension[R] Magazine has been reporting on the benefits of metformin since the early 1990s. While metformin has been available for use in Europe since the 1950s, the drug was not approved by the FDA for use in the United States until 1994.
* Curr Cancer Drug Targets. 2015 Dec;15(1).
(Life Extension; November 2015 pg.22)
There are things you should know about starting Metformin.
The main issue that people have with Metformin is that it hits their stomachs like a bomb*. In many cases all that's needed is patience and their bodies will calm down and it will become more tolerable. The trick is to titrate it slowly. I started with a 500mg tablet which was too hard on my stomach so I cut it in half and spent 2 weeks getting used to it. It also helped to take it with my largest meal of the day, which for me was lunch (Metformin can irritate an empty stomach). I upped that to 500mg a day which again started irritating my stomach. I went to see my wonderful doctor about this (she wasn't really happy about putting a non diabetic on this drug....but having reviewed the studies I brought her) she put me on a time released Metformin (Glumetza) which made all the difference in the world. After a month on Glumetza we upped the dose to 1000mg which is a therapeutic dose for a diabetic. I contacted Ellen Davis and asked her to contact Dr. D'Agostino and ask how much I should be taking for my weight. He emailed back that I should be on no more than 1000 to 1500mg a day. (Since there's no information out there through studies you really have to rely on the experience of those on the cutting edge of this field.)
When you take extended release Metformin there is an issue of when the drug levels are most released into your blood stream. That's not so important if you aren't a diabetic but, it builds up and has a cumulative effect on your fasting blood sugar after you take it for a week. If you miss a dose you will see a small but immediate difference in your post meal blood sugars. But if you stop taking it for a week you will not only see that effect the day after you stop it but you will also see a second notable increase in your fasting blood sugar and pre-meal sugar about a week later.
If you want to change the time when you take an extended release Metformin there is one rule you must follow: Don't ever take MORE than your full prescribed dose during a 24 period. That is because your body has an exquisitely sensitive feedback system whose job is to push blood sugar back up as soon as it senses that the blood sugar has dropped by more than 20 or 30 mg/dl (1.70 to 2.2 mmol/L) below your usual fasting blood sugar level. When this happens, this system kicks in with dramatic effect. It does this by secreting "counter-regulatory hormones" which are your old friend the stress hormones. You might experience FALSE Hypoglycemia. This process may get your pulse pounding, your sweat pouring and your body feeling as if you'd just narrowly escaped becoming a predator's lunch. A check of your blood sugar will show that you are nowhere near true hypoglycemia (sometimes it's even higher than your "normal" blood levels), but your body thinks it's been hit by hypoglycemia.
When your heart is pounding and you are feeling shaky and faint, it is very tough to do nothing, especially since your body is helpfully suggesting that all would be well if you'd just scarf down some nice carbohydrates to solve the problem. The reason this happens is that by the time you feel the impact of those stress hormones they have already signaled your liver that it needs to dump a load of glucose into your blood stream to raise your blood sugar to correct the false hypoglycemia. Be careful that when this happens that you don't sabotage yourself by reacting to the symptoms by ingesting carbs in the belief that you are fighting a life threatening bout of hypoglycemia. Mild Hypoglycemia is one that sends your blood sugar no lower than 65mg/(3.9 mmol/L) It is not life threatening, but can be very unpleasant. I have spent time in the bathroom with diarrhea and vomiting when my blood sugar was only in the 70's. Ellen Davis suggest that you take a sip of orange juice if your symptoms are really unbearable. I wish I would have found her book "Fight Cancer With a Ketogenic Diet" two months earlier than I did.
*Side Effects - The main disadvantage of metformin is its gastrointestinal side-effects. About 1 in 3 people who take metformin experience significant incidents of diarrhea, gas, nausea, vomiting, or bloating. Because it can be difficult to predict when these distressing side effects will occur, this can have a major negative impact on a person's quality of life. These unpredictable GI side effects cause many people to discontinue metformin. On the other hand, many people use metformin without significant GI issues, so its effect really varies from person to person. To lessen the occurrence of GI side effects, metformin is started at lower doses and gradually increased, the "start low and go slow" approach. GI side effects are supposed to disappear within 4-8 weeks once a final dosage is established, but most people find that they recur periodically anyhow. Those prone to IBS (Irritable Bowel Syndrome) issues seem particularly sensitive. GI issues are lessened if metformin is taken with a meal (especially their largest meal of the day), and GI incidents are significantly reduced with the extended release version of metformin. Pro-biotics also help.
There are more than 2700 (no this isn't a typo) government studies listed in PubMed about Metformin and Cancer
The ones that interested me were:
There is even one in my neighborhood; a Phase III trial to compare invasive disease free survival of patients with early stage Breast Cancer with Metformin VS Placebo. (I wasn't going to wait around for the results of this one. There was enough 'evidence out there for me to be on it.)
Plain English various study results
I use a product called Glumetza (this is the only product I have found that doesn't give me side effects because it uses a new technology MOD*). It is not availible in a generic form at this time. The cost in the USA is astronomical, so I get it from Canada at YouDrugStore .