Cancer Treatment & Prevention with Metformin
Metformin is a 'common' insulin sensitizing drug which is FDA approved to be used to treat diabetes. Diabetes is a 'minor' market for this absolutely amazing drug! First, and foremost: if a person does not have diabetes, Metformin can not abnormally lower blood sugar. So, we're talking here, about a very safe drug to use. Next, Metformin is an insulin sensitizing agent: it helps you use your own body's insulin more effectively. Biggest side effect: you burn energy more efficiently and you lose weight or you keep your weight down!
So, why aren't you hearing about Metformin on the radio and on TV if it's so good for preventing cancer and heart disease, and that there's more to it than just diabetes? Because Metformin went generic a few years ago and you can get it for $10 for 90 days of treatment, at Walmart (if you have no insurance). The company lost the patent: there's no huge profits to be made, so there's no huge advertising budget! So, right now you're reading about one of the most amazing drugs in all of history, right here!
Metformin is an absolutely AMAZING drug which positively affects no less than 256 metabolic pathways in the body. Previous to our current findings below, Metformin had been proven to treat or prevent 6 different cancers. Today that number of cancers exceeds a dozen, and the list is expanding and only has hopes of continuing to expand!
We're not talking about a 2-3% reduction in cancer risk, but instead we're looking at massive 40-60% reductions in cancer growth, as well as an equal or better amount of 40 to 90% in preventing cancers! In all of recorded time, there has never been a drug this safe, this potent, in preventing cancer, and this potent in curing cancer and preventing heart disease. While most people are afraid of the painful death cancer can cause, most Americans will die from heart attacks. Heart attacks, non-fatal and fatal are also reduced by 40 to 60% by Metformin! Metformin can also be used with almost any cancer agent (for treatment) and increases the agent's effectiveness by 40-75%! Read on.
Before we get to the great articles below, and how they might help you or a family member, let's talk for a moment about Metformin and insulin. Insulin allows sugar to enter the billions of cells in the body. Without insulin, the blood sugar level rises, and the cells starve. So, insulin is a key player in getting energy to cells. That said, as each of us age, we lose some sensitivity to our ability to use our own insulin effectively.
Loss of insulin sensitivity not only results in elevated blood sugar, it results in elevated levels of insulin. Elevated insulin or hyperinsulinemia results in a number of adverse and age-accelerating diseases and effects including hypercholesterolemia, hypertension, atherosclerosis and obesity. This 'group' of symptoms has been called 'Syndrome X'. By improving insulin sensitivity by: a low carbohydrate diet, continuous moderate physical activity for 30-45 minutes for 6 of 7 days/week, and taking Metformin can drastically improve insulin sensitivity and may alleviate many of the adverse metabolic changes as well as reduce weight to a more ideal number.
Can Metformin make you 'look' better? Yes it can! Metformin will increase collagen, which improves skin elasticity. Feel better, be better, and look better- what a combination! Then, best of all reduce risk for heart attack and cancer by taking Metformin, and you've got the 'whole' package!
Below, we're providing some of the dozens of scientific studies, over the past decades, which prove that Metformin is the greatest 'wonder drug' ever brought to market! Want to prevent your aunt or uncle from getting lung cancer? How about breast cancer? Ovarian cancer? What, exactly, would you do to help a loved one to NOT get cancer? How about preventing that heart attack? Would you bring them by the office, so we can get them started and prevent horrible suffering and a premature death?
Each of the articles, below, cites a specific scientific article from a research journal. Each article has an easy to understand summary. We next present some of the scientific and bio-chemical talk behind how the science works. These reports will discuss some of the 256 metabolic pathways Metfomin uses to help people. What beauty there is in science!
Long Term Metformin Use Associated with Decreased Risk of Breast Cancer
From the journal: Diabetes Care. June 2010, vol 33 (6) P 1304-1308
Summary: In looking at 22,621 women with diabetes, there was a 44% reduction in the risk of getting breast cancer, in those women who took Metformin, who ranged in age from 55 to 75, versus those who did not use Metformin.
Study Specifics (science): Using the UK based General Practice Research Database; a 'nested' case-controlled study was conducted on 22,621 females on diabetic meds. One group took Metformin, the other did not. Patients in both groups were matched by sex, age, calendar time, general practice, and multivariate conditional logistical regression analyses and were further adjusted for use of oral diabetes drugs, insulin, estrogens, smoking, BMI, diabetes duration, and Hemoglobin A1C (average blood glucose as calculated every 90 cumulative days).
Results: 305 patients developed breast cancer. The mean age at cancer development was 67.5 years (+/- 10.5 years) at time of diagnosis. Seventeen patients on Metformin developed breast cancer versus 120 who were not on Metformin. That's seven times as many women who developed breast cancer, by not being on Metformin! There were 168 women with 'confounding' data who were excluded from the final analysis. In summary: we see a 7 fold reduction in breast cancer between the group on Metformin versus the non-Metformin group!
Metformin Attenuates (weakens) the Stimulatory Effect of a High Energy Diet on In Vivo (living tissue testing) for LLC1 (Lung) Carcinoma Growth
From the journal: Endocrinology Related Cancer: Sep 2008, vol 15(3) p 833-839
Summary: In looking at mice, which were genetically altered to express human genes and gene sensitivities, we fed them an ultra rich diet, normally associated with increased lung cancer risk. Next we broke them into four groups: in the first, we gave the mice Metformin and a 'regular diet'; the second, we gave a 'rich' diet associated with cancer and Metformin; the third, a regular diet and no Metformin, and the fourth a 'rich' diet and no Metformin.
By day 17, mice in the 'rich' diet had tumors twice the size of those on the 'regular' diet group. But the size was significantly smaller in the 'rich' diet plus Metformin. In mice on a 'regular' diet, Metformin had no effect on tumor growth.
Study Specifics & Results: Metformin attenuated the increased insulin receptor activation associated with high-energy diets and also led to increased phosphorylation of AMP Kinase, two different actions which would be expected to decrease neoplastic proliferation. The findings are consistent with prior epidemiological studies where Metformin reduced cancer risk and improved cancer prognosis.
Metformin: New Understandings, New Uses
From the Journal: Drugs, 2003, Vol 63 (18), p1879-1894
Summary: Metformin improves insulin sensitivity, lowers weight, improves blood sugar numbers, reduces the incidence of heart disease, prevents and treats Polycystic Ovarian Syndrome (PCOS), and decreases all causes of organ damage in large blood vessels in diabetics.
Study Specifics: reducing cardiovascular and other vascular disease in diabetics will prevent heart attacks and prevent leg and foot amputations. The evidence of success is obvious, the exact pathophysiological and biochemical pathways are yet to be identified fully (as of 2003). The massive benefits of Metformin are obvious.
Decreased Mortality Associated with the use of Metformin Compared with Sulfonylurea Monotherapy in Type 2 Diabetics
From the Journal: Diabetes Care, Dec 2002, (12) p2244-2248
Summary: Sulfonylurea diabetic drugs are famous for causing people to develop abnormally low blood sugars and to go into a coma. Back in the 1970's, before we knew better, it was believed that diabetics 'just needed more' insulin and they'd be 'fine'. Injectable insulin had been around for decades, but sulfonylurea diabetic drugs promised to 'pound' the pancreas to make even more insulin. The claimed benefit was the ability to increase insulin without using insulin shots. Fallacy, not fact, prevailed in the 70's. What diabetics first lose is the ability, the sensitivity, to use insulin. Insulin production is lost later, but the ability to effectively use insulin is the critical point to understand. Enter Metformin.
Metformin was the first, safe, insulin sensitizing agent. It would improve and normalize blood sugar, and best of all- it was impossible for Metformin to cause blood sugar to go too low. In fact, as part of the research on the drug, people without diabetes were put on Metformin to prove it would not abnormally lower blood sugars.
In this study, they looked at 12,272 diabetics over an average 5 year period. Death from all causes: cancer, heart disease and so on was 40% lower in the Metformin group.
The Specifics: the adjusted odds ratio (OR) for all cause mortality for Metformin monotherapy was 0.60, compared with sulfonylurea monotherapy. Sulfonylurea plus Metformin combination therapy was associated with all-cause mortality of 0.66. A specific risk reduction in all cause cardiovascular related deaths was noted.
Metformin Inhibits Aromotase Expression in Human Breast Adipose Stromal Cells Via Stimulation of AMP-activated Protein Kinase
From the journal: Med Hypotheses: Oct 2009, 73(4) p 606-607
Summary: Breast cancer is the most common malignancy diagnosed in women. Insulin hormone is one reason why breast cancer reoccurs and why it causes death in breast cancer survivors. Targeting insulin therapy is one treatment not undertaken by most oncologists. Specifically, in HER-2 breast cancer, Metformin can be used for prevention and treatment.
The Specifics: According to molecular classification and subclassification, basal like and HER-2 positive breast cancers have the worst outcomes with standard chemotherapy. Clearly, a 'best practices' approach which incorporates the chemotherapeutic benefits of Metformin is a mandatory step in 'adjunctive' therapy beyond 'standard' chemotherapy for Her-2 breast cancer. Insulin plays a critical biochemical pathway in HER-2 occurrence and re-occurrence. Using Metformin to target and signal a cascade of proliferative and anti-apoptotic events in the cancer cell is critical. Specifically, it can not be argued that Metformin causes HER-2 suppression via the inhibition of mTOR in breast cells. The time has arrived for oncologists to target insulin reduction and to alter HER-2 oncogene based molecular pathogenic steps in breast cancer by safely using the potent benefits of Metformin!
Is It Time for Metformin to Take Place in Adjunctive Treatment of HER-2 Positive Breast Cancer? Teaching New Tricks to Old Dogs.
From the Journal: Breast Cancer Res Treat., Sept 2010, 123(2) p 591-596
Summary: Several chemical elements and proteins have been shown to improve the prevention of breast cancer from estrogens being produced in the breasts themselves. Metformin suppresses these key critical bad actors, thus preventing breast cancer at the source! Metformin can be used to prevent breast cancer as well as improve treatment of breast cancer.
The Specifics: AMP-activated protein kinase (AMPK) is recognized as a master regulator of energy homeostasis. In association with AMPK-kinase LKB1, it's been shown to provide a molecular link between obesity and postmenopausal breast cancer via its' actions to inhibit aromatase expression, and therefore estrogen production within the breast.
Metformin is known to increase the activity of AMPK and to inhibit aromatase production in human breast adipose stromal cells. Results of the study show Metformin significantly decreases forskolin/phorbol ester (FSK/PMA)- induced expression of aromatase. The actions of Metformin to significantly increase phosphorylation of AMPK at Thr172. Metformin also increased LKB1 protein expression and promoter activity which provided an additional mechanism by which Metformin activates AMPK. Metformin also inhibits the nuclear translocation of CRTC2, a CREB-coactivator known to increase aromatase expression and is a direct down-stream target of AMPK. Individually, and in summary these results show that Metformin reduces the local production of estrogens within the breast, thereby providing a powerful tool most cancer specialists are not using and are unaware of! Metformin can be used to prevent breast cancer in all women, but especially in obese women, and can be further used to enhance any chemotherapy regimen in the treatment of breast cancer!
Metformin and Cancer: Doses, Mechanisms and the Dandelion and Hormetic Phenomena
From the journal: Cell Cycle: March 201, 9(6) p21
Summary: In the early 1970's Professor Vladamir Dilman developed the idea that antidiabetic biguanides (such as Metformin) may be promising geroprotectors and anticancer drugs. Since the 2000's, every researcher involved in evaluating Metformin has concluded that a vast array of cancers, including HER-1 and HER-2, which are nasty resistant breast cancers, would benefits from treatment with Metformin. Metformin targets stem cells which are originators of cancer cell lines, as well as targeting numerous metabolic pathways at many steps of cancer evolution which are involved in the body. The researchers advise that instead of being an antidiabetic medication, Metformin should be labeled by the science community as an 'anti-cancer pill'.
The Specifics: In the early 2000's Anisimov's experiments revealed that chronic treatment of female transgenic HER-2-/neu mice with Metformin significantly reduced the incidence and size of breast adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have shown Metformin significantly reduces cancer incidence and improves cancer patient's survival in type 2 diabetics. Metformin is getting reset and relabeled as an anticaner therapy!
Metformin constitutes a novel anti-cancer hybrid pill to metabolically fight cancer. Metformin combines the long-lasting effects of antibodies by persistently lowering levels of blood insulin and glucose and the intermediate potency of a cancer cell-targeting molecular agent by suppressing the pivotal AMPK/m TOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER-1 and HER-2. In even low doses, Metformin targets the cancer-initiating stem cells from which tumor cells develop, thereby preventing the original cancer, as well as preventing a cancer relapse. When used in combination with cytotoxic chemotherapy (Dandelion Hypothesis-yank it out by the root) Metformin is very promising and proven. By acting as an efficient caloric restriction mimetic, Metformin enhances the capacity of mitotically competent cells to self maintain and repair (homeostasis). There is no valid scientific reason to omit Metformin from any chemotherapy regimen of any cancer, especially breast cancers.
Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure
From the journal: Diabetes Care 2005 Oct, 28(10) p2345-51
Summary: Metformin is 'officially' contraindicated in patients with heart failure due to a potential for lactic acidosis: but is the concern valid? Conclusion: Metformin is very safe in diabetics with heart failure and resulted in an 87% improvement in reducing death when patients with heart failure took Metformin.
The Specifics: 12, 272 new diabetics were enrolled in the study. Of this 12, 272, there were 1,833 with heart failure. The average of patients was 72 years, and 57% were male. Compared with 'standard' 1970's sulfonylurea therapy there were 404 people who died on 'standard' therapy, whereas there were only 69 who died in the Metformin group- that's the huge 87% difference! Then there were those who were hospitalized: 658 on 'standard' therapy, and only 160 on Metformin- a 76% improvement!
Conclusion: Metformin should NOT be contraindicated in diabetics, or others, with heart failure, rather it should be given to reduce hospitalizations and death.
Metformin Attenuates Ovarian Cancer Cell Growth in an AMP-Kinase Dispensable Manner
From the journal: Journal of Cell Mol Med. 2009 Oct 29
Summary: Metformin significantly inhibited proliferation of diverse chemo responsive and chemo resistant ovarian cancer cell lines. The details below clearly show Metformin is clearly an anti-proliferative therapeutic agent to be used in those with ovarian cancer.
The Specifics: Metformin activates AMP-activated protein kinase (AMPK) which regulates cellular energy metabolism. Ovarian cell lines: VOSE, A2780,CP70, C200, OV202, OVCAR3, SKOVip, PE01, and PE04 predominantly express -alpha1, -beta-1, -gamma1, and -gamma2 isoforms of AMPK subunits. The studies clearly show Metformin treatment significantly inhibited proliferation of diverse chemo-responsive and-resistant ovarian cancer cell lines (A2780, CP70,C200,OV202,OVCAR3,SKVO3ip,PE01 and PE04) caused cell arrest accompanied by decreased cyclin D1 and increased p21 protein expression and activated AMPK in various ovarian cancer cell lines as evidenced by increased phosphorylation of AMPK alpha and its downstream substrate ACC (acetyl Co-carboxylase) and enhanced beta oxidation of fatty acid as well as by attenuated mTOR-S6RP phosphorylation, which inhibited protein translational and lipid biosynthetic pathways, showing Metformin is a certain inhibitor of ovarian cancer cells. Metformin mediated effect on AMPK is dependant upon LKB1 (liver kinase B1) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 null mouse embryo fibroblasts (mefs). This conclusion was supported by using siRNA approach to downregulate LKB1 in ovarian cancer cells. Metformin inhibited cell proliferation in both wild type and AMPK alpha 1/2 nul mefs as well as in AMPK silenced ovarian cancer cells.
Conclusion: The results prove Metformin is an anti-proliferative therapeutic agent which can act upon both AMPK dependant as well as independent pathways, being highly effective in ovarian cancer treatment and prevention.
New Users of Metformin are at Low Risk of Incidental Cancer: A Cohort Study Among People with type 2 Diabetes
From the journal: Diabetes Care: 2009 Sep 32 (9) p 1620-1625
Summary: In looking at 8, 170 patients 1/2 on Metformin, 1/2 not; the Metformin group during the years 1994-2003 had 64% fewer cancers of all types develop.
The Specifics: Metformin has anti-diabetic properties via AMP-activated pathways which cause increased cellular sensitivity to insulin. These same pathways also suppress tumor formation and inhibit abnormal cell growth. In a survival analysis, using Cox regression: 7.3% of those on Metformin versus 11.6% of those not on Metformin developed cancer over a 10 year period. The adjusted hazard ratio was 0.46 (CI 95%).
Conclusion: An overall 64% reduction in all cancers over a 10 year period is HUGE! As some European scholars have already advised: Metformin should be changed form a 'Diabetic' classed drug to an 'Anti-cancer' classed drug!
Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-dependent Manner
From the journal: Cell Metab. 2010 May 5 11(5) p90-401
Summary: Two varied pathways are known to allow Metformin to reduce cancer growth: TSC1/2 and AMPK. What this study showed, is that of the 256 metabolic pathways which Metformin favorably affects, there is another cancer pathway which is disrupted independent of TSC1/2 and AMPK.
The Specifics: Regulation on mTORC1 is achieved through the integration of multiple inputs, including those of mitogens, nutrients and energy. It was thought that agents which increase the cellular AMP/ATP ratio, such as Metformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or independent mechanisms. Unexpectantly, it was discovered that Metformin inhibited mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. The surprise: Metformin inhibited mTORC1 activation and signaling dependent upon Rag GTPases.
Conclusion: In two distinct clinical trials, as well as the study above, Metformin acted to suppress mTORC1 signaling in an AMPK-independent manner. This shows another pathway Metformin uses to suppress cancer.
Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical trial
From the journal: Cancer Prev Res (Phila PA) 2010 Sep 3 (9) 1077-1083
Summary: The authors have previously shown the chemopreventive effect of Metformin in two rodent models of colorectal carcinogenesis. The specifics of development of cancer are discussed and proven in the previous rodent models, and correlate with other human studies, supporting the use of Metformin for prevention of colorectal cancer.
The Specifics: The objective of the study was to evaluate the chemopreventive effect of Metformin on Rectal Aberrant Crypt Foci (ACF) which are endoscopic surrogate markers of colorectal cancer. While only 26 non-diabetic patients were studied, a 42% reduction in ACF was noted at month one. The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in Metformin patients. This is the first human study to show a reduction in colorectal cancer in humans on Metformin in a placebo controlled trial.
Conclusion: Prior observational studies, rodent studies, and now short term human studies confirm that Metformin prevents colorectal cancer, and at a 42%rate! Also, the use of ACF formation was proven to be accurate for such study.
Metformin Prevents Tobacco Carcinogen-Induced Lung Tumorigenesis
From the journal: Cancer Prev Res (phila Pa) 2010 sep 3 (9) p 1066-1076
Summary: Metformin prevents certain initial cancer pathways from activating, in the mouse model, in both lung cancer and liver cancer. the pathways activated in lung cancer caused by tobacco, Metformin prevented the cancer activation.
The Specifics: Activation of mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen-induced lung cancer. therapies which target mTOR could prevent or serve as treatment for lung cancer. Metformin activated AMP-activated protein kinase (AMPK) which can inhibit the mTOR pathway. To confirm this hypothesis, A/J mice were treated with oral Metformin after exposure to the known tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Metformin reduced lung tumor burden by up to 53% at steady states which are achievable in humans. mTOR was inhibited in lung tumors, but only modestly. in the liver, Metformin activated AMPK and inhibited mTOR. In lung tissue, Metformin did not activate AMPK, but inhibited phosphorylation of insulin-like growth factor-1 receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK) and mTOR. these actions suggest Metformin indirectly inhibited mTOR in lung tissue by decreasing activation of IGF-1R/IR and Akt upstream of mTOR. Based upon these unique findings, intrapertioneal Metformin was administered and resulted in a 72% decreased tumor burden, which corresponded with decreased cellular proliferation and marked inhibition of mTOR in tumors.
Conclusion: Metformin prevents tobacco carcinogen-induced lung cancer and should be clearly used as a chemotherapy preventive agent in ALL smokers.
Metformin Extended release Treatment of Adolescent Obesity: a 48 Week Randomized, Double Blind, Placebo Controlled trial with 48 week Follow-up
From the journal: Arch Ped Adoles Med. 2010 Feb 164(2) p116-123
Summary: While the above articles cite preventing heart disease and preventing cancer by using Metformin, there remain a number of diseases associated with obesity. Does Metformin, extended release help with obesity, especially in teens- a very hard to reach group. In a study that spanned 4 years (2003-2007) the active Metformin group achieved a decrease of BMI by 0.9, while the placebo group increased BMI by 0.2.
The Specifics: The numbers cited above tell the story, and at a follow-up of 48 weeks the numbers held, showing both short and long term benefits. While a 1.1 difference in BMI is not huge, the trajectory the differences pose, may well persist and reveal numerous benefits to those on Metformin. But, as with many studies we've critiqued over the years, only treating the weight component in obesity is only one factor. While Metformin helps reduce weight, are these kids doing any activity other than lying on the couch eating potato chips and ice cream while watching TV as too many teen do? We really need to stay focused on the 'whole person' concept whenever we discuss weight, diabetes, lipids, and hypertension.
Conclusion: A decent quality study which shows Metformin helps teens to control obesity and obesity related diseases further down the road.
Metformin Selectively Targets Cancer Stem Cells and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission
From the online journal: Cancer Res 2009 sep 14 (doi:10.1158/0008-5472.CAN-09-2994)
Summary: 'Mary' has surgical removal of her cancerous upper left breast, followed by 'standard' radiation and chemotherapy; but never takes Metformin. Five years later Mary has a 'spot on her lung', and a biopsy shows its metastatic breast cancer. How did that happen? Simple- Mary did not take Metformin. Stem cells, those little buggers that create every cell type in the body can become cancerous, and will continue to generate cancer. Only Metformin will destroy stem cell cancer lines- that's HUGE!
The Specifics: In looking at the cancer that scares women most: breast cancer, a huge discovery has been made. the cancer stem cell hypothesis suggests that, unlike most cancer cells within a cancerous tumor, cancer 'stem cells' resist chemotherapy and can regenerate the various cell types in the tumor- as in they never stop this process, causing what seems to be a 'relapse' while in reality, represent a continuous generation of cancerous cells, but too small to initially measure by presently detection methods. Hence, people are told they're 'cured' when in fact the cancer stem cells persist, which accounts for the high cancer reoccurence rates at 5 years. So drugs which specifically target cancer stem cell lines are a huge discovery- with the best therapy being Metformin. Whether use alone or in combination with chemotherapy, Metformin caused a huge drop in cancer reoccurance in breast cancer. Low doses of Metformin were provided to selectively kill cancer stem cell lines in 4 different types of breast cancer in a xenograft mouse model for breast cancer. Two months later (decades in mice age) the mice remained cancer free with the Metformin single or combination therapy.
Conclusion: This study firmly supports the cancer stem cell hypothesis and further provided critical rationale for using Metformin alone or with any chemo therapeutic agent to improve patients long term outcome with breast cancer, and likely every other cancer as well, as the science of Metformin's effects on cancer remain consistent in multiple layers of disassembly of cancer cells, and cancer stem cells. The most critical point: there is no other reasonably cost effective agent (like Metformin) which reduced cancer risk and destroys stem cell cancer lines- nothing!