Can I take metformin for my cancer?

March 25, 2022

Dear Ketooncologist,

What are your thoughts on using metformin for cancer?

Sincerely,

A Veteran’s wife

Dear Veteran’s wife,

Metformin is receiving a lot of publicity lately, as far as being a possible new “cure for cancer”.

The basics about METFORMIN

Metformin began in 1918 as a traditional European herbal medication called Galega officinalis (also known as goat's rue). It was found to be rich in guanidine, an organic compound derived from guano, (literally bird and bat poop!) and found to be able to lower blood glucose. Later, insulin and other glucose lowering drugs were discovered and metformin lost popularity for a time, until recently it came back into favor.

Because metformin does not normally cause weight gain or hypoglycemia (dangerously low blood glucose), it is currently the preferred first-choice oral blood glucose-lowering drug used today to treat type 2 diabetes. Metformin is a pill and is also known as Glucophage, Glucophage XR, Glumetza, Fortamet, or Riomet.

When the body senses that glucose is scarce, the liver finds a way to make it (official scientific term is gluconeogenesis or glucose-new-generation). The newly made glucose is then released it into the bloodstream. (This reminds me of my teenage son. He loves bread, but because we try not to buy any, he learned how to make bread from scratch!)

Once in the bloodstream, glucose then makes its way into cells where it can then be used for energy.

Metformin can decrease liver production of glucose as well as help glucose that is in the bloodstream, move into cells. It becomes particularly helpful in type 2 diabetics, because there is a lack of responsiveness to insulin and therefore glucose accumulates because it has a hard time exiting the blood and there is poor uptake into cells.

Does metformin have anti cancer properties? 2,3,4,5,6

Metformin activates the enzyme called AMPK (AMP-activated protein kinase). Other ways of activating AMPK is via caloric restriction, fasting, or resistance exercise. 2

What is AMPK and how does AMPK and metformin help fight cancer?

AMPK is a tumor suppressor. If tumor suppressors are dormant or malfunctioning, cancers may grow.

AMPK also cuts back on inflammation, and controls the amounts of fats in the body by stimulating fatty acid oxidation. Inflammation can trigger cancer.

AMPK also reprograms our metabolism by acting on molecules that control cell growth and signaling. When AMPK is suppressed, the pro-cancer tumor signaling pathways (such as Raf/ERK/RSK pathways) are activated!

Metformin, just like AMPK, can also inhibit tumor survival pathways and can also inhibit glycolysis (glycolysis is the main energy source of cancer cells) itself. If you like to read scientific journals, you might be familiar with “mTOR signaling”. mTOR is a nickname for “mammalian target of rapamycin, which is just a fancy term for a type of cancer signal that exists within the body. It so happens to be a common signal that fuels cancer cells to grow and multiply. It is similar to the Raf/ERK/RSK pathway that I just mentioned above. They are all signaling pathways that are pro-cancer. Metformin however tends to mainly affect the mTOR pathway, which in turn, stimulates the insulin and insulin growth factor receptor pathway, which is involved in cancer development and maintenance. There are many more pathways and signals involved in cancer, and they all communicate with each other in some way, but I won’t discuss this further because it will take hours.

Just remember, AMPK maintains normal metabolism. Normally, the body senses the lack of energy, or lack of oxygen (hypoxia) and activates AMPK, to maintain the overall metabolism of the normal body. When something goes wrong, there is a loss of this self defense checkpoint and AMPK fails to activate, causing cancer to emerge.

AMPK also helps normalize glucose levels by helping the body accept the good effects of insulin, and help making one “insulin sensitive”. Type 2 diabetics often have the opposite. They are “insulin insensitive” and often have overproduction of “reactive oxygen species” which can damage our DNA, which can lead to mutations and ultimately, cancer . When the body becomes insensitive to insulin (type 2 diabetics), it does not realize it (insulin) is already there, as if it is invisible, the body continues to try to rev up more insulin by increasing IGF-1 (insulin like growth factor). Too much IGF will stimulate production of even more hormones that stimulate cell growth , AND also prevents cell death. So in the end, there is an imbalance between cell growth and cell death. Too much cell growth plus cell multiplication outpaces cell death, and cancers are born. 1,2

Metformin can enhance insulin sensitivity (through AMPK )which then can improve glucose uptake (glucose moving out of the blood and into the cells) and thus improve blood glucose levels.

Many studies show that the risk of some cancers (pancreas, liver, colon) are reduced in type 2 diabetic patients treated with metformin.

Preliminary studies show that there are cancer fighting properties in certain drugs such as aspirin and metformin /antidiabetic drugs that can be effective in human cancers. 2,3,4.5.6

Making energy (ATP) less available for cancer

There is lab data to support the theory that low glucose plus metformin can enhance metformin’s anti-cancer effects. In the lab, scientists examined cancer cells in petri dishes and cell cultures and found that metformin can actually kill cancer cells.

In a study of breast cancer and ovarian cancer cells , they found that when metformin is given when glucose levels are high, the cancer cells did not die. But when they lowered glucose , the metformin became more effective in killing cancer. And vice versa, in cells that were unresponsive to metformin in the presence of high glucose, when they lowered the glucose levels they found that the cancer fighting effects got better. The reason behind this was proposed to be that metformin + low glucose enhanced metformin’s negative effect on ATP production. Less ATP, means less fuel for glycolysis, and less glycolysis, meant less energy to cancer cells, and therefore more cancer cell death.

Decreased tumor signaling with metformin + low blood glucose

Low glucose plus metformin also meant increased inhibition of tumor survival signaling pathways. There is a lab model (in vivo and in vitro) where cancer cells treated with metformin and grown in low glucose medium can kill more cancer cells by decreasing ATP production , inhibition of survival signaling pathways as well as strengthen inhibition of glycolysis itself.

What about using metformin in addition to chemotherapy?

Metformin is not FDA approved for treating cancer. However, many studies in human cancers are on their way. Enrollment in a clinical trial not only is safer for you, but the knowledge gained can infinitely help benefit others.

https://clinicaltrials.gov/ct2/results?cond=Cancer&term=metformin&cntry=&state=&city=&dist=

In summary, metformin is a drug for treating diabetes , but it is not a standard drug for cancer. At least not yet. Ask your doctor how you can improve your blood glucose and whether metformin is right for you.

All the best,

Dr. Tan

  1. Arcidiacono, Biagio et al. “Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms.” Experimental Diabetes Research 2012. Experimental Diabetes Research. Web.
  2. Dreyer et al Resistance exercise increases AMPK activity and reduces 4E BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physic. 2006 Oct 15; 576(Pt 2): 613-624.
  3. Faubert, Brandon et al. “AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth in Vivo.” Cell Metabolism 17.1 (2013): 113–124. Web.
  4. Zhuang, Yongxian et al. “Mechanisms by Which Low Glucose Enhances the Cytotoxicity of Metformin to Cancer Cells Both in Vitro and in Vivo.” PLoS ONE 9.9 (2014): n. pag. PLoS ONE. Web.
  5. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009 Aug;137(2):482-8.
  6. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncology. 2010 Mar; 6(3): 457-470
  7. Quinn BJ, Kitagawa H, Memmott RM , et al. Repositioning metformin for cancer prevention and treatment. Trends Endocrine Metab 2013;24:469-80

Guanidine- an organic compound derived from guano - https://www.britannica.com/science/guano

Exploring the Link Between Cancer and Weight Loss:

March 14, 2024
Breaking Down the Fear  Ketogenic diets often result in weight loss. Cancer patients frequently lose weight. Does this mean that keto diets are harmful to use in cancer patients? Cancer and weight loss are two topics that often come hand in hand, yet the relationship between them can be complex and sometimes frightening. Weight loss, particularly unexplained or rapid, can evoke fear in many individuals, often signaling underlying severe health concerns. However, when it comes to cancer, weight loss can sometimes be one of the earliest signs of the disease. In today's blog, we delve into the connection between cancer and weight loss, unraveling why the latter often instills fear and how understanding this relationship can lead to better health outcomes. Understanding Cancer and Weight Loss: Cancer involves uncontrolled cell growth and abnormal spread of cells throughout the body. These invading cells affect various organs and systems and disrupt their normal function. Weight loss can be very subtle or profound depending on the type of organ invaded. As cancer takes root and establishes itself, it also spews out cytokines (unique inflammatory proteins) that also serve as signal messengers, signaling muscles to lose volume, resulting in a weight loss phenomenon known as cachexia. Cachexia is a complex syndrome. Inflammation is often at the root of this problem, of profound muscle wasting, generalized fatigue, and poor appetite, Why Are We Afraid of Weight Loss? Weight loss, in general, is often perceived negatively in society. There's a prevailing notion that thinness equates to health, beauty, and success, while weight loss may imply illness or a lack of control. However, when weight loss occurs without intentional dieting or exercise, it can be a red flag for underlying health issues, including cancer. In cancer, especially, the presence of weight loss is disturbing because we traditionally associate it with illness. Association with Illness: Unexplained weight loss is commonly associated with illness, particularly severe conditions like cancer. The fear of the unknown and the potential implications of such weight loss can be daunting for individuals. To be of "normal" weight is equated with health. Loss of Control: Weight loss, especially rapid or involuntary, can make individuals feel like they've lost control over their bodies. This loss of power can be unsettling and exacerbate feelings of anxiety or fear. Uncertainty: Weight loss without a clear cause can be perplexing and raise questions about what might happen within the body. The uncertainty surrounding the underlying cause can contribute to fear and anxiety. During chemotherapy, however, weight loss is inevitable because we are in a catabolic state. The active cancer is making us lose weight. The key is to control or snuff out the underlying cancer. Once you weaken the tumor, less cytokine release and less inflammation will follow. As this occurs, the "source" of the cytokine release will die, and weight gain should naturally recover. Therefore, loading up on carbohydrates to make us appear to be of "normal weight" is incorrect. Loading up on sugary treats will only strengthen the cancer and will only be counterproductive! Conclusion: The fear of weight loss, particularly in the context of cancer, is understandable, given the potential implications for health and well-being. However, by understanding the complex relationship between cancer and weight loss and challenging societal stigmas, we can accept some form of healthy weight loss during chemotherapy. We can learn to recognize unhealthy weight loss (loss of muscle mass) and differentiate it from healthy weight loss during a ketogenic diet (most of which is weight loss from fat and excess water). As long as one feels energetic, with normal blood parameters and no indication of significant liver or kidney failure, anemia, or marrow failure, then some healthy weight loss during chemotherapy or implementation of a ketogenic diet CAN be acceptable.

GINGER ALE DURING CHEMOTHERAPY

March 4, 2024
Are you still drinking "ginger ale" during your chemotherapy sessions? You know, those gleaming, chilled cans of sparkly soda that your cheerful chemotherapy nurse hands out along with your anti nausea pills?  The scent and the taste of ginger help nausea stay away. But did you know that your "ginger ale" contains no ginger? Worse, the HFCS high fructose corn syrup, a highly processed sugar, can do you more harm than good. And making your cancer cells really happy. Next time you go for your chemo session, ask for water instead. Or better yet, bring your own ginger-infused drink from home. Here is some background about ginger. For centuries, ginger has been used as a remedy for nausea and digestive issues, and some scientific evidence supports its effectiveness. Here are some examples. Morning Sickness: Pregnant women often experience morning sickness, and ginger has been traditionally used to alleviate these symptoms. Several studies have shown that ginger can reduce nausea and vomiting during pregnancy. For example, a meta-analysis published in the Journal of Obstetrics and Gynaecology Research in 2014 concluded that ginger supplementation significantly reduced the severity of nausea and vomiting in pregnant women without any significant side effects. Motion Sickness: Ginger is effective in reducing motion sickness. A study published in Aviation, Space, and Environmental Medicine 1986 found that ginger was more effective than a placebo in reducing symptoms of motion sickness. Subsequent studies have supported these findings, suggesting ginger can alleviate symptoms like nausea, vomiting, and cold sweating associated with motion sickness. Chemotherapy-Induced Nausea: Cancer patients undergoing chemotherapy experience nausea and vomiting. The Journal of Alternative and Complementary Medicine 2009 published a review that analyzed several randomized controlled trials and found that ginger supplementation could reduce the severity of chemotherapy-induced nausea. Postoperative Nausea: Nausea and vomiting are common after surgery. A meta-analysis published in the journal Integrative Cancer Therapies in 2012 found that ginger effectively reduced postoperative nausea and vomiting compared to a placebo. However, we need more research to fully understand its mechanisms and best dosage. Everyone responds differently, but ginger, in its natural form, is usually safe to take during chemotherapy. Just make sure its the real thing! Photo credit Dan Sorum @ unsplash

Welcome to all our new members

January 30, 2023
Welcome to all our new members

Getting Started On A Keto Diet

May 17, 2022
Getting started on the keto diet usually sounds like someone is trying to lose weight? When you add cancer to that recipe, it becomes a whole new ball game. Do any of these thoughts sound familiar? “ I want to fight my cancer , and I heard that this diet can help me heal “ “ I’m confused because the keto diet will make me lose weight” “I’m afraid to lose more weight.” “I can’t afford to lose weight! “ “When is weight loss just right, and when is it too much? “ Is there real hope for me? Over the past two decades, I’ve seen my share of cancer patients. Yup, the whole package - diagnosis, anxiety, chemo, radiation, hair loss, weight loss, and, failures. But, I also saw many patients who achieve clean CT scans, remission, happy news, hair growth, and of course, the coveted weight gain. I have my own collection of patients with stage four cancers, a few have actually reached their ten to twelve year anniversary with me. Most of them have made it past five years and some are in complete remission. Yes, stage four to stage zero! How did they do it? You may have come to this website, searching for answers. I wish that I could tell you all that I know, in one sentence, but I can’t. It usually takes me several office visits to educate my patients. For now, you can stick around, and try to absorb the knowledge from current posts. Take time to read through my past blogs. Signup for a keto conference. There is one coming up very soon. The MHS 2022 in Santa Barbara California. May 5 to 8. Read books, and more books. You might be surprised. Not all books are the same. Some are full of dense material, while some are mostly fluff. But eventually, you will find the right book for you. Join me in one of my subgroups. But you need to fit the profile and be past the beginners stage when you join. Or you might get bored! I do show up there from time to time, to break the ice. And by the way, when you are stuck and can’t find the answers you are looking for...you need to make your voice heard and post your questions. What if my cancer doctor doesn’t approve? If your cancer doctor doesn’t know much about the keto lifestyle, or about metabolic approaches to cancer, don’t lose hope. Try to educate them, Share your knowledge. Even if they are at first resistant, with time, some will marvel at your progress and will notice that you are doing better than their average patients. Finally... the number one question that shows up on my blog.... What diet is best for me? I’m so CONFUSED! “ Dr. XXX on YouTube said that a keto diet and weight loss is good for cancer, but another doctor YYY said the opposite, that I should eat, healthy carbs, more plants, fruit , avoid fat and protein, try to gain weight. “ Dr. WWW advocates a vegan diet, but Dr ZZZ said do a carnivore diet.... , help!!!! Let me know your thoughts in the comments below!

New drug for relapsed Glioblastoma, a deadly form of brain cancer

March 30, 2022
There is exciting news on the horizon for glioblastoma, which is a deadly form of brain cancer. Have you heard of activated T cell therapy? It is similar to the car-T cell therapies that you often hear about for blood cancers. Well, this form of therapy is now available for patients with brain cancers. The catch is, you must enroll in a clinical trial. It is not yet available to the public. To qualify, one must have glioblastoma, a form of brain cancer , and cancer must have relapsed after the first diagnosis. Patients who are interested are now able to ask for information about enrolment at the Cedars Sinai Medical Centre in Los Angeles. This trial will be classified under a Phase one type of clinical trial. The drug company, Kairos pharma is the sponsor. This exciting new therapy, otherwise known as KROS 201, is a form of activated T cell therapy. The patient’s white blood cells are first harvested. Blood is removed by a simple intravenous blood draw, and then sent off to the lab to be processed in a cell culture. In the lab, the white blood cells are primed by exposing them to small protein substances called cytokines. This process will in turn activate the white blood cells, specifically the killer T cells. Once activated, these cells can now fight cancer by inactivating cancer stem cells. The T cells are returned to the patient’s body by intravenous infusion. The link for enrolment is not yet available but do keep checking on www.clinicaltrials.gov

Mistletoe plus chemotherapy in non small cell lung cancer

March 25, 2022
Iscador, a type of mistletoe preparation was tested by a medical team in Israel alongside conventional chemotherapy in the treatment of patients with advanced non small cell lung cancer. Although no improvement in survival or quality of life was noted,non hematological side effects from the chemotherapy and hospitalizations were less in the group which received the mistle toe preparation. Possible yet unproven mechanisms of action include improvement of immune function via increasing the number of NK natural killer cells as well as improve the function of Tumor Necrosis Factor Alpha. Fever which is also a noted side effect of this preparation has been described prior to spontaneous regression of certain cancers such as melanoma implying a possible role of immunotherapy in the fight against cancer. No randomized trials on cancer patients have yet been published. 

Brain cancer – Challenges with the ketogenic diet

March 25, 2022
We made little progress in the way of survival in the treatment of malignant brain tumors, specifically the deadly glioblastoma multiform. Despite aggressive surgery followed by radiation therapy and precautionary chemotherapy, they relapse early and survival is measured in months. Patients rarely survive beyond a year. Alternative therapies abound with few successes. Some patients attempt to enroll in clinical trials in search of new drugs that might make a difference in their survival.  There is a biologic treatment available. It is the monoclonal antibody called Bevacizumab. It supposedly controls the growth of blood vessels that supply nutrition to the brain tumor. Shrinking the blood supply supposedly starves the tumor. Very exciting, but nonetheless isn't a cure. Long term survivors still remain a rarity. There is mounting interest in metabolic basis of cancer development. In this respect, I do feel that ketogenic diets have potential benefit in brain cancer patients. The role of sugar and carbohydrates in the progression of brain tumors is interesting. Since most patients also are on steroids to improve brain swelling. It is also bad for them because this also increases their blood glucose. I wonder, if we are indeed adding fuel to the fire. A few case reports of brain tumor patients who were offered the ketogenic diet showed that some tumors stopped growing while others improved their survival. Notably, upon discontinuation of the diet, the tumor was noted to again progress, only to regain control upon reinitiation. Currently there are 4 clinical trials ongoing in the United States involving the ketogenic diet in the treatment of various forms of cancer. Another is ongoing in Germany. More clinical trial participation is desperately needed if we are going to move ahead and forge any progress with this deadly cancer. =

Lonsurf, newly approved colon cancer drug

March 25, 2022
Three weeks ago I got word that another new chemotherapy drug has been approved for the treatment of colorectal cancer. Ideal candidates for this drug are patients who failed previous chemotherapy involving one of the following drugs: 5-Fluorouracil, Oxaliplatin, Irinotecan, Cetuximab (also known as Erbitux) and Avastin ( also known as Bevacizumab).This new drug has two active components, trifluridine and tipiracil. Trifluridine is a new nucleoside analog. In other words, a nucleoside is a nitrogen containing biologic compound linked to a sugar, which when phosphorylated, turns into a nucleotide, which is a vital part of the DNA backbone. Trifluridine therefore is a nucleoside analog, meaning it isn't but acts like a nucleoside. It incorporates itself into the DNA structure and interferes with cell growth and proliferation. Tipiracil inhibits the enzyme thymidine phosphorylase, which catalyzes the degradation of Trifluridine, thus allowing it to last longer. Thymidine phosphorylase by itself has pro-angiogenic properties, meaning it promotes blood vessel formation and encourages better blood supply of tumors, so Tipiracil directly stops this advantage. Furthermore, Tipiracil by stopping thymidine phosphorylase, prevents the formation of thymine and 2-deoxy-alpha-D-ribose 1-phosphate. 2DARP is a strong reducing sugar product of thymidine catabolism and causes increased oxidative stress within tumors, promotes release of more tumor blood vessel promoting factors ( angiogenic growth factors) such as interleukin-8, vascular endothelial growth factors VEGF, and matrix metalloproteinase-1 an enzyme which breaks down collagen and extracelular matrix, which is key in promoting tumor metastases. This three mode action of tipiracil ( inhibits thymine production, thymidine phosphorylase VEGF activity, stops ROS and MMP-1 , VEGF and cytokine production)- makes it more attractive since it can potentiate the action of the common colorectal chemotherapy drug 5- fluorouracil whose main action is to inhibit formation of thymine. The RECOURSE trial, a —international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer apparently resulted in statistically significant improvement in overall survival and progression free survival . The drug is given orally, twice a day, for two straight weeks, minus weekends, followed by a two week break. Side effects are listed as anemia, neutropenia, asthenia/fatigue, nausea, —thrombocytopenia, decreased appetite, diarrhea,vomiting, abdominal pain,—pyrexia. Since it is barely a month since FDA approval ( Sept. 24, 2015) it still has not hit our pharmacy shelves. I am however eager to try this. Will update you again in a few months. 

Getting into ketosis

March 25, 2022
How long does it take to get into a state of clinical ketosis? By ketosis, I mean the levels of beta-hydroxybutyric acid reaching to above normal levels yet not high enough to bring you into a medical emergency such as ketoacidosis. As little as a day is all it takes. You an achieve this in different ways. The most common and sure fire method is to simply stop eating. If you fast and only limit your intake to water or sugarless herbal , which technically has ZERO calories, you will achieve a state of ketosis in no time. Another way is to try fasting for 15 hours a day, or roughly, just eat one full meal daily. this should bring you into ketosis too, though not all 24 hours are involved. If you try a ketogenic diet, that means, you will be limiting your carbohydrate intake to approximately 20% of your total daily intake, and take the rest in the form of fats ( 70-75%) and proteins (5 to 10%).  Monitoring your progress will be helpful. A simple glucometer will suffice. Individual serum Ketone sticks, readily available from Amazon.com or special order through your pharmacy can be used to check your ketone levels throughout the week.

Update on clinical trials of the ketogenic diet in cancer

March 25, 2022
Several clinical trials are ongoing throughout the United States at the moment.  The University of Iowa Department of Radiation Oncology is running a couple of Phase I trials on the use of the ketogenic diet plus radiation and chemotherapy in head and neck cancers, and they also have another which studies the ketogenic diet plus chemoradiation in non-small cell lung cancers and pancreatic cancer. Michigan State University has one which recruited brain cancers, also known as glioblastomas, a very deadly type of brain cancer. Duke University recently began a randomized trial studying the ketogenic diet plus androgen deprivation therapy in prostate cancer , using the ketogenic diet versus a control standard diet. Unfortunately per recent info posted on the clinicaltrials.gov website, the trial was terminated as of December 2015, due to lack of funding, and due to the principal investigator leaving . Closer to home, the Veterans Affairs Medical Center in Pittsburgh has their own trial which recently concluded in 2015. This trial recruited patients with advanced solid tumors across broad tumor types and patients dieted up to 16 weeks or until tolerated. The results have not yet been publicly released as it is currently under manuscript review.
More Posts