Metformin in Combination with a Ketogenic Diet as an effective Cancer Protocol

Metformin originates from the French lilac or goat’s rue (Galega officinalis, see picture below), a plant used in folk medicine for several centuries including for diabetes and other ailments. Today, the use of Metformin has been shown to decrease the risk of cancer. (1) Metformin has exhibited a strong and consistent antiproliferative action on several cancer cell lines, including breast, colon, ovarian, pancreatic, lung, and prostate cancer cells. (See Exhibits A & B below). These in vitro studies were generally completed by preclinical studies showing a reliable antitumoral effect in various mouse models. In addition, the first clinical trials demonstrated a beneficial effect in breast and colon cancer. (2) Metformin has also shown to increase radiotherapy’s efficiency. (3)
COMBINING A LOW GLUCOSE KETOGENIC DIET WITH METFORMIN
Would it be possible to potentiate metformin’s anti cancer impact within a low glucose environment ? It has been shown that different cancer cells exhibit altered sensitivity to metformin treatment. (CF Exhibit B) One reason for this discrepancy is the common cell culture practice of utilizing high glucose. However, when glucose is lowered, metformin becomes increasingly cytotoxic to cancer cells. In low glucose conditions ranging from 0 to 5 mM, metformin was cytotoxic to breast cancer cell lines MCF7, MDAMB231 and SKBR3, and ovarian cancer cell lines OVCAR3, and PA-1. (4)
Recent findings suggest that lowering glucose potentiates metformin induced cell death by reducing metformin stimulated glycolysis. Additionally, under low glucose conditions metformin significantly decreased phosphorylation of AKT and various targets of mTOR, while phospho-AMPK was not significantly altered. (5) Furthermore in vivo studies using the 4T1 breast cancer mouse model confirmed that metformin inhibition of tumor growth was enhanced when serum glucose levels were reduced via low carbohydrate ketogenic diets. (6)
MECHANISMS OF ACTION
Metformin decreases hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis). (7) However, the complete molecular mechanisms of action metformin generates is incompletely understood, especially in carcinogenesis. Among other possible explanations and mechanisms of action, Research identifies the following pathways: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP), and consequent activation of protein kinase A (PKA), inhibition of mitochondrial glycerophosphate dehydrogenase and a gut microbiota connection. (8, 9, 10) For malignancies, metformin’s principle anti-cancer mechanism of action in a low glucose micro-environment is based on cancer’s decreasing ATP production and the inhibition of it’s survival signaling pathways.
HISTORY
While training at the Hôpital de la Pitié, French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from Galega officinalis, which is related in structure to metformin and had seen brief use as an antidiabetic before the synthalins were developed. (11) Later, working at Laboratoires Aron in Paris, he was prompted by Garcia’s report to reinvestigate the blood sugar-lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name “Glucophage” (glucose eater) for the drug and published his results in 1957. (12)
 BOTANICAL GLUCONEOGENESIS INHIBITORS
While integrative oncology is more and more integrating metformin within physician’s protocols and patients are even going to Mexico to purchase it without a medical prescription, holistic oncology tends to prefer natural molecules in their unprocessed state. In this field, there are many antidiabetic botanicals which could be used with the ketogenetic diet, even Ayahuasca, but under herbalist, nutritionist and medical supervision given the possible biochemical plant interaction.
Among others, one of the Institute’s favorite botanical, Black Seed, (Nigella sativa) and its oil could  be used as well as curcumin, both could be integrated within this protocol because both nigella sativa  (13) and curcumin not only work on inflammatory, hormonal and immune pathways, but they can also have a significant effects on blood glucose (EXH C). Like wise with cinnamaldehyde (CA), (one of the active components of cinnamon), this molecule has been known to exert several pharmacological effects such as anti-inflammatory, antioxidant, antitumor as well as antidiabetic and antiadipogenic effects (ie, through modulation of the PPAR-γ and AMPK signaling pathways cf. EXH D)  and of course the Galega herb, but in small amounts given its’ alkaloids’ toxicity. One peer reviewed study showed that Galega caused a significant reduction in body weight in both normal and genetically obese  animals treated for 28 days when compared with respective controls. (EXHIBIT E)
CONCLUSION: ACRI RECOMMENDS A LOW-GLUCOSE KIETOGENIC DIET IN COMBINATION WITH METFORMIN AND POSSIBLY OTHER GLUCONEOGENESIS INHIBITORS IN AN ADJUNCTIVE MANNER
The in vitro, in vivo and clinical data supports the judicial and individualized use, under medical supervision, of metformin with a kietogenic diet. Metformin causes few adverse effects when prescribed appropriately (the most common is gastrointestinal upset) and has been associated with a low risk of having a low blood sugar (hypoglycemia).  (14) Lactic acidosis (a buildup of lactate in the blood) can be a serious concern in overdose and when it is prescribed to people with contraindications, but otherwise, no significant risk exists. (Cf metformin’s side effects).  Small amounts of antidiabetic botanicals could also be combined, including French lilac (galega of.) (15) but the precautionary principle needs to be observed given biochemical interactions.
Pending more conclusive findings with metformin, botanicals, kietogenic and even metabolic agents like   dichloroacetate interactions, the sole metformin-kietogenic diet combination would appear to be relatively safe, we have  anecdoctal and  preclinical findings to confirm this. (EXHIBIT F)  However,  this protocol should be guided under the competent supervision of a health-care practitioner who has clinical nutrition and eventually confirmed via clinical trials. (16)
While this protocol could be a “stand-alone” for exceptional candidates, given cancer cells adaptive resiliency, we recommend that this protocole be an adjunctive one to be cautiously used in synergy with other metabolic, integrative and holistic techniques.
Screen Shot 2015-04-24 at 5.34.39 PM
PRECISION AND REFERENCE NOTES
(1) Malek, M; Aghili, R; Emami, Z; Khamseh, ME (2013). “Risk of Cancer in Diabetes: The Effect of Metformin.”. ISRN endocrinology 2013: 636927.
(2)Ben Sahra I, Le Marchand Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug?. Mol Cancer Therapeutics. May 2010;9(5):1092–99.
(3) Impairment of oxidative phosporylation by metformin may increase the efficiency of radiotherapy by preventing the production of reactive oxygen species. Van Gisbergen, M. W.; Voets, A. M.; Starmans, M. H.; De Coo, I. F.; Yadak, R; Hoffmann, R. F.; Boutros, P. C.; Smeets, H. J.; Dubois, L; Lambin, P (2015). “How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models”. Mutation Research/Reviews in Mutation Research 764: 16–30.
4 PLoS One. 2014 Sep 25;9(9):e108444. doi: 10.1371/journal.pone.0108444. eCollection 2014.
Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo.
Zhuang Y1, Chan DK2, Haugrud AB1, Miskimins WK1.
5 Ibid.
6 Ibid.  Ketogenic diet is based on good fats that produce ketones. Ketone is a chemical produced when there is a shortage of insulin in the blood and the body breaks down body fat for energy. Ketones in the urine is a sign that your body is using fat for energy instead of using glucose because not enough insulin is available to use glucose for energy.
(7) Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update [PDF]. Ann Intern Med. 2002;137(1):25–33. The “average” person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.
(8) Rena G, Pearson ER, Sakamoto K (September 2013). “Molecular mechanism of action of metformin: old or new insights?”. Diabetologia 56 (9): 1898–906. doi:10.1007/s00125-013-2991-0. PMC 3737434. PMID 23835523.
(9)  Jump up to: 
a b Burcelin R (July 2013). “The antidiabetic gutsy role of metformin uncovered?”. Gut 63 (5): 706–707. doi:10.1136/gutjnl-2013-305370. PMID 23840042.
(10) 
 Madiraju, Anila K.; Erion, Derek M.; Rahimi, Yasmeen; Zhang, Xian-Man; Braddock, Demetrios T.; Albright, Ronald A.; Prigaro, Brett J.; Wood, John L.; Bhanot, Sanjay; MacDonald, Michael J.; Jurczak, Michael J.; Camporez, Joao-Paulo; Lee, Hui-Young; Cline, Gary W.; Samuel, Varman T.; Kibbey, Richard G.; Shulman, Gerald I. (21 May 2014). “Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase”. Nature 510 (7506): 542–546.
(11) Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes International. 2004;21(3):115–7
(12) Campbell IW. Metformin—life begins at 50: A symposium held on the occasion of the 43rd Annual Meeting of the European Association for the Study of Diabetes, Amsterdam, The Netherlands, September 2007. The British Journal of Diabetes & Vascular Disease. 2007;7:247–252.
(13). Abdullah O Bamosa, Huda Kaatabi, Fatma M Lebdaa, Abdul-Muhssen Al Elq, Ali Al-Sultanb. Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. Indian J Physiol Pharmacol. 2010 Oct-Dec;54(4):344-54.
(14)  Lipska KJ, Bailey CJ, Inzucchi SE (June 2011). “Use of metformin in the setting of mild-to-moderate renal insufficiency”. Diabetes Care 34 (6): 1431–7.
(15)  This bee plant and as green manure plant known as French Lilac, prevalent in the ACRI French center,  when used judiciously can be useful,  despite it being classified as a noxious weed. Its name derives from gala (milk) and ago (to bring on), as Galega has been used as a galactogogue in small domestic animals (hence the name “Goat’s rue”).  G. officinalis has been known since the Middle Ages for relieving the symptoms of diabetes mellitus. Upon analysis, it turned out to contain compounds related to guanidine, a substance that decreases blood sugar by mechanisms including, but not limited to a decrease in insulin resistance. But these molecules were too toxic for human use. Georges Tanret identified an alkaloid from this plant, galegine, that was less toxic, and this was evaluated in unsuccessful clinical trials in patients with diabetes in the 1920s and 1930s.  Later on,  related compounds were investigated thanks to which biguanide drugs like metformin were produced.  Cf. Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P (eds). 2007. Metformin: the Gold Standard. A Scientific handbook; Chichester: Wiley. Chapter 1: Galegine and anti diabetic plants
(16). Of the 40 clinical trials on ketogenic diets, none appear to be tested in combination with metformin.
EXHIBIT A
Mol Pharm. 2015 Oct 2. [Epub ahead of print]
Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment.
Sui X1,2, Xu Y1, Wang X1,2, Han W1,2, Pan H1,2, Xiao M3.
Metformin, a biguanide derivative that is widely used for treating type 2 diabetes mellitus, has recently been shown to exert potential anticancer effects. Many retrospective data and laboratory studies suggest the idea that metformin has antineoplastic activity, but some other studies reach conflicting conclusions. Although the precise molecular mechanisms by which metformin affects various cancers have not been fully elucidated, activation of AMPK-dependent and AMPK-independent pathways along with energy metabolism aberration, cell cycle arrest and apoptosis or autophagy induction have emerged as crucial regulators in this process. In this Review, we describe the role of metformin in the prevention and treatment of a variety of cancers and summarize the molecular mechanisms that are currently well documented in the ability of metformin as an anticancer agent. In addition, the scientific and clinical hurdles regarding the potential role of metformin in cancer will be discussed.
EXHIBIT B
PLoS One. 2014 Sep 25;9(9):e108444. doi: 10.1371/journal.pone.0108444. eCollection 2014.
Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo.
Zhuang Y1, Chan DK2, Haugrud AB1, Miskimins WK1.
Different cancer cells exhibit altered sensitivity to metformin treatment. Recent studies suggest these findings may be due in part to the common cell culture practice of utilizing high glucose, and when glucose is lowered, metformin becomes increasingly cytotoxic to cancer cells. In low glucose conditions ranging from 0 to 5 mM, metformin was cytotoxic to breast cancer cell lines MCF7, MDAMB231 and SKBR3, and ovarian cancer cell lines OVCAR3, and PA-1. MDAMB231 and SKBR3 were previously shown to be resistant to metformin in normal high glucose medium. When glucose was increased to 10 mM or above, all of these cell lines become less responsive to metformin treatment. Metformin treatment significantly reduced ATP levels in cells incubated in media with low glucose (2.5 mM), high fructose (25 mM) or galactose (25 mM). Reductions in ATP levels were not observed with high glucose (25 mM). This was compensated by enhanced glycolysis through activation of AMPK when oxidative phosphorylation was inhibited by metformin. However, enhanced glycolysis was either diminished or abolished by replacing 25 mM glucose with 2.5 mM glucose, 25 mM fructose or 25 mM galactose. These findings suggest that lowering glucose potentiates metformin induced cell death by reducing metformin stimulated glycolysis. Additionally, under low glucose conditions metformin significantly decreased phosphorylation of AKT and various targets of mTOR, while phospho-AMPK was not significantly altered. Thus inhibition of mTOR signaling appears to be independent of AMPK activation. Further in vivo studies using the 4T1 breast cancer mouse model confirmed that metformin inhibition of tumor growth was enhanced when serum glucose levels were reduced via low carbohydrate ketogenic diets. The data support a model in which metformin treatment of cancer cells in low glucose medium leads to cell death by decreasing ATP production and inhibition of survival signaling pathways. The enhanced cytotoxicity of metformin against cancer cells was observed both in vitro and in vivo.
EXHIBIT C
Curr Top Med Chem. 2015;15(23):2445-55.
Curcumin: A Natural Product for Diabetes and its Complications.
Nabavi SF, Thiagarajan R, Rastrelli L, Daglia M, Sobarzo-Sanchez E, Alinezhad H, Nabavi SM1.
Curcumin is the yellow-colored bioactive constituent of the perennial plant, Curcuma longa L., which possesses a wide range of physiological and pharmacological properties such as antioxidant, anti-inflammatory, anticancer, neuroprotective and anti-diabetic activities. Anti-diabetic activity of curcumin may be due to its potent ability to suppress oxidative stress and inflammation. Moreover, it shows a beneficial role on the diabetesinduced endothelial dysfunction and induces a down-regulation of nuclear factor-kappa B. Curcumin possesses a protective role against advanced glycation as well as collagen crosslinking and through this way, mitigates advanced glycation end products-induced complications of diabetes. Curcumin also reduces blood glucose, and the levels of glycosylated hemoglobin in diabetic rat through the regulation of polyol pathway. It also suppresses increased bone resorption through the inhibition of osteoclastogenesis and expression of the AP-1 transcription factors, c-fos and c-jun, in diabetic animals. Overall, scientific literature shows that curcumin possesses anti-diabetic effects and mitigates diabetes complications. Here we report a systematical discussion on the beneficial role of curcumin on diabetes and its complications with emphasis on its molecular mechanisms of actions
EXHIBIT D
J Agric Food Chem. 2011 Apr 27;59(8):3666-73. doi: 10.1021/jf104814t. Epub 2011 Mar 22.
Cinnamaldehyde prevents adipocyte differentiation and adipogenesis via regulation of peroxisome proliferator-activated receptor-γ (PPARγ) and AMP-activated protein kinase (AMPK) pathways.
Huang B1, Yuan HD, Kim do Y, Quan HY, Chung SH.
Cinnamaldehyde (CA), one of the active components of cinnamon, has been known to exert several pharmacological effects such as anti-inflammatory, antioxidant, antitumor, and antidiabetic activities. However, its antiobesity effect has not been reported yet. This study investigated the antidifferentiation effect of CA on 3T3-L1 preadipocytes, and the antiobesity activity of CA was further explored using high-fat-diet-induced obese ICR mice. During 3T3-L1 preadipocytes were differentiated into adipocytes, 10-40 μM CA was treated and lipid contents were quantified by Oil Red O staining, along with changes in the expression of genes and proteins associated with adipocyte differentiation and adipogenesis. It was found that CA significantly reduced lipid accumulation and down-regulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding proteins α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1) in concentration-dependent manners. Moreover, CA markedly up-regulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and these effects were blunted in the presence of AMPK inhibitor, compound C. In the animal study, weight gains, insulin resistance index, plasma triglyceride (TG), nonesterified fatty acid (NEFA), and cholesterol levels in the 40 mg/kg of CA-administered group were significantly decreased by 67.3, 55, 39, 31, and 23%, respectively, when compared to the high-fat diet control group. In summary, these results suggest that CA exerts antiadipogenic effects through modulation of the PPAR-γ and AMPK signaling pathways.
EXHIBIT E
J Pharm Pharmacol. 1999 Nov;51(11):1313-9.
Novel weight-reducing activity of Galega officinalis in mice.
Palit P1, Furman BL, Gray AI.
Galega officinalis (galega, Goat’s Rue, French Lilac) is well known for its hypoglycaemic action and has been used as part of a plant mixture in the treatment of diabetes mellitus. During pharmacological investigations of an ethanolic extract of a powdered mixture of equal proportions of G. officinalis, Cressa cretica, Mangifera indica and Syzygium jambolanum, a weight reducing effect of galega was discovered. In this study we have investigated the novel weight reducing effect of galega in mice. Galega herb (10% w/w in the diet) caused a significant reduction in body weight in both normal and genetically obese (ob/ob) animals treated for 28 days when compared with respective controls (P < 0.01). In normal mice, the weight loss was reversible and initially associated with a transient reduction in food intake but was then maintained even in the presence of increased eating above the control level. Pair-fed normal mice receiving galega for seven days also showed significant weight loss (P < 0.01, compared with the control) in the presence of increasing food intake. In sharp contrast, weight loss in galega-treated ob/ob mice was accompanied by a persistent reduction in food intake over the 28-day treatment period. Post-mortem examinations of all galega-treated mice revealed a striking absence of body fat. Serum glucose was significantly reduced in both strains of mice receiving galega for 28 days (P < 0.01), whereas serum insulin was significantly reduced only in obese mice (P < 0.01). In summary, together with its established hypoglycaemic effects, galega has a novel weight reducing action that, in normal mice, is largely independent of a reduction in food intake. The mechanism of the weight reducing action of galega is unclear but involves loss of body fat.
EXHIBIT F
Med Hypotheses. 2011 Aug;77(2):171-3.
The complete control of glucose level utilizing the composition of ketogenic diet with the gluconeogenesis inhibitor, the anti-diabetic drug metformin, as a potential anti-cancer therapy.
Oleksyszyn J1.
In the animal models of glucose dependent cancer growth, the growth is decreased 15-30% through the use of low-carbohydrate, calorically restricted and/or ketogenic diet. The remaining growth depends on glucose formed by the liver-kidney gluconeogenesis as is the case in the cancer cachexia. It is hypothesized that a new treatment for cancer diseases should be explored which includes the ketogenic diet combined with the inhibition of gluconeogenesis by the anti-diabetic drug metformin.

MetforminPlant

Galega officinalis has been traditional anti-diabetes relief medicine for centuries. Serious toxic side effects though have been witnessed.  (Witters L. The blooming of the French lilac. J Clin Invest. 2001;108(8):1105–7) Picture is licensed under the Creative Commons Attribution 3.0 Unported license
Copyright (c) Advanced Cancer Research Institute and agents. All rights reserved.
DISCLAIMER. This educational article should not be construed as medical advise. Furthermore, ACRI recommends to never  use Galega Officinalis to self treat a high glucose symptomatology.

Advanced Cancer Research Institute’s Director, Christian Joubert, has contributed in the coming and edification of a needed spiritual civilization by working as a professor of international public law in France and at Gonzaga Law School as well as in holistic medicine and other disciplines in different universities and institutes for most of his adult life. In association with his activities in clinical practice, organic agriculture, eco-development, community building, he has also actively participated via litigation and education in the legal protection of internationally recognized human rights, focusing on the protection of fundamental health rights and medical freedoms. He is presently working on a documentary and a book on Holistic Oncology, both of which have been designed to promote the necessary paradigm shift that will forever replace today's outdated, dogmatic, ideological and bankrupted conventional oncology model with progressive, evidence-based, sustainable and resilient holistic standards of care that are much more efficient, safe and cost-friendly than what persists in today's mainstream. See link on mission for more details.

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