Gluconeogenesis & How Hydrazine Could Help Fight Cancer and Cachexia

First I will start with the conclusion of this post, also added at the end of the post:

Conclusion:

Gluconeogenesis is a mechanism that needs to be addressed specifically in advanced cancer patients that are seeing fast loss of body mass.

One major way to reduce Gluconeogenesis is via oral administration of Hydrazine. This is a tool with great potential. However, since it has also some potential side effects, I would only use it in emergency case, when wight loss is present and can not be inhibited in any other way .

When I find time, I will search for other Gluconeogenesis/PEPCK inhibitors that have less or no side effects.

Background:

This article addresses one of the aspects I think is of major relevance in cancer. That is gluconeogenesis.

I find this subject extremely important, specifically in case of advanced cancers, as it is connected with several important points I’ve observed during the past years:

  • during the advanced stage, cancer patients see their weight declining fast
  • this is concomitant with an increase of systemic inflammation
  • this is concomitant with increase of blood glucose level
  • this is concomitant with increased tumor activity

I was specifically triggered by the increase of blood glucose level for most of the cancer patients in advanced stage, as I did not understood exactly why at some point suddenly, the blood glucose jumps to a high level and remains there and may not be controlled by the diet. I think this is a very important event, which if we could understand and find ways too inhibit its occurrence, we could be able to strongly interfere with cancer progression.

Now, after spending some time diving deeper into the related scientific literature and connecting various pieces of information, things start to make sense.

Indeed, it is well known that inflammation is a state of the human body in which cancer can become more active and in turn produce more inflammation (Ref.1, Ref.2). It is the same point when markers are jumping up, as seen in the blood results of many cancer patients and it is correlated with a CRP increase and tumor marker increase. Here is a relevant Youtube video where Dr. Vikas P. Sukhatme at MIT in Cambridge, MA, explains the very important role of inflammation in cancer progression.

In relation to inflammation level in patients, white cell counts such as neutrophil, lymphocyte and platelet counts and acute phase proteins, such as C-reactive protein and albumin and their combinations, neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) respectively have been all reported repeatedly to have prognostic value (Ref.).

Among many negative aspects of inflammation, one aspect that it is specifically relevant in advanced cancers is related to the fact that inflammation triggers the activation of the hypothalamic-pituitary-adrenal (HPA) axis (Ref.). This is the same axis that is activated by stress and the result is that the adrenal gland will start producing cortisol and release it into the blood stream. In turn, cortisol (which is a glucocorticoid) activates a systemic response in the human body leading to a loss of skeletal muscle mass, which is also a hallmark of cachexia (Ref.). Skeletal muscle mass loss can also be triggered by other processes, including release of IL-6 following inflammation (Ref.). Elements resulted from the breakdown of muscle mass, are converted by the liver in glucose, facilitated by a mechanism called gluconeogenesis which is also activated by the cortisol. Gluconeogenesis, is the process through which the human body can start burn body mass during starvation, in order to obtain glucose – the much needed source of energy (Ref.). This is the same mechanism that makes us loose weight during periods of high stress.

So now we have the link between various events explaining the observations listed above under the bullet points. Therefore, in line with the scientific literature, the flow of events would be like this:

  • Inflammation triggers the activation of HPA axis and release of IL-6 (Ref.1, Ref.2)
  • Activation of HPA axis triggers Cortisol production (Ref.)
  • Release of IL-6 also triggers Cortisol production (Ref.)
  • Cortisol & IL-6 triggers systemic loss of body mass & increased Gluconeogenesis (Ref.1, Ref.2, Ref.3)
  • Gluconeogenesis leads to increase of Blood Glucose while “processing” the body mass (Ref.)
  • Increased Blood Glucose leads to increase of tumor activity (Ref.)
  • Increased tumor activity leads to higher inflammation (Ref.)

Increase of tumor activity, not only induces more inflammation but it also increases the production of lactic acid (Ref.), which next to the breakdown of body mass, represents additional fuel for the activated Gluconeogenesis, leading to additional glucose released into the blood.

So essentially, inflammation triggers an avalanche-like effect in terms of tumor evolution.

Now that we understand the link between various events, we can start to think on how we can stop this chain of events. While we can think of many approaches, including inhibition of inflammation such as discussed in this Reference or in this Video, in this post I will focus on Gluconeogenesis as a very important target to address when fighting cancer. Because it is a key mechanisms that facilitates the above chain reaction, the goal is to understand how Gluconeogenesis works and what are the tools we have in our hands to inhibit the underlining mechanisms, or at least substantially reduce it in order to reduce or stop cachexia and at the same time tumor evolution.

Gluconeogenesis inhibition should be relevant for most cancer patients, regardless of the tumor type. However, the most visible positive impact of Gluconeogenesis inhibition should occur in advanced cancers, since large tumors are expected to strongly rely on that.

Before discussing inhibitors of Gluconeogenesis, I will first dive a bit into the related science. Those who do not have the interests to understand that, may want to skip the “Mechanism” section and go to the next section to find out what are the potential “tools” to interfere with Gluconeogenesis.

Mechanism:

Gluconeogenesis

  • a process through which human body (but also plants, animals, fungi, bacteria, and other microorganisms) can generate glucose from other substrates such as lactate, glycerol, and glucogenic amino acids (e.g. glutamine).
  • takes place mainly in the liver
  • intensified during periods of fasting, starvation, low-carbohydrate diets, or intense exercise

Gluconeogenesis supports tumor development in two different ways:

  • Gluconeogenesis in the liver: Tumors use glucose to produce energy via fermentation (see Warburg effect Ref.). As a result of the fermentation, tumors also produce lactate that is eliminated by the cell (together with some protons as lactic acid) part of which may finally end up in the blood. When Gluconeogenesis is activated, that lactate absorbed from blood (but also the elements resulted from the body mass breakdown as discussed above) can be turned back into glucose inside the liver. This glucose is released back in the blood, and finally absorbed by tumors to further fuel their growth. Next to this process, as discussed above, tumor progression also leads to systemic loss of body mass, that in turn represents fuel for Gluconeogenesis, finally converted in glucose.
  • Gluconeogenesis in the tumor cells: In addition to the above, a Gluconeogenesis like process can also take place inside the cancer cell (Ref.). When the cancer cells are deprived of glucose they can directly absorb lactate (produced and eliminated by the fermenting cancer cells) and convert that into energy to support their development. In this case, lactate is absorbed via MCT1 transporter, which is the same transporter that also enables the anti cancer effects of 3-Bromopyruvate. It is important to note, that in contrast to fermentation, the conversion of lactate into energy in this case requires functional mitochondria and access to oxygen. This is why, I expect that these types of cancer cells are typically located at the region towards the tumor surface, or more specifically, closer to the blood vessels.

A key enzyme enabling Gluconeogenesis is called PEPCK (Phosphoenolpyruvate carboxykinase) (Ref.). This enzyme is of two forms depending on its location within the cell:

  • PCK1 (the cytosol isoform of PEPCK-C) (Ref.) and
  • PCK2 (the mitochondrial isoform of PEPCK-M)

In humans 50% of the liver PEPCK activity is mitochondrial (caused by PCK2), and 50% is cytoplasmic (caused by PCK1) (Ref.). Here is a Figure showing one of PEPCK roles inside the cell https://www.nature.com/articles/s41598-017-11613-2/figures/4

PCK1 is regulated by insulin, glucagon and glucocorticoids (such as cortisol). During starvation, glucagon enhances expression of PCK1 (to maintain the required blood glucose level), while cortisol does that during stress (to activate the body fight mode). Specifically, the rate of transcription of the PCK1  gene is

  • increased by glucagon (via cAMP) and glucocorticoids (Cortisol) and
  • is inhibited by insulin from the blood (secreted by pancreas when blood glucose is high – used by the body to e.g. manage the glucose spikes after meals)

Therefore, in healthy humans PCK1 activity is inversely regulated by glucose concentrations in the blood (Ref.). In this (Ref.) PhD thesis, page 49, there is a good figure showing the known intracellular signalling pathways leading to PEPCK expression.

Interestingly, the fact that many advanced cancer patients are found with high blood glucose levels, puts them in a similar category with type II diabetes, where the blood glucose level remains high even if the blood insulin level is high. This is in contrast to the normal human body reactions, and it is called insulin resistance. Now that we’ve got to the point indicating that cancer patients may suffer from insulin resistance, I just searched the literature and indeed there is an association between some types of cancers and type II diabetes (ref.). Consequently, a very relevant subject to be investigated is “insulin resistance”, which I think could be the lead towards other approaches to inhibit cancer, such as fasting (known as an approach to reduce insulin resistance). 2DG is a substance that seems to have an insulin reduction potential via an increase in sensitivity to insulin (Ref.). Yet, for now I will park this subject. Also note that the body’s mechanism to adjust insulin sensitivity is via the growth hormone (Ref.). For those interested to read more on insulin resistance, here is a very nice article addressing that (Ref.).

Back to gluconeogenesis: since elevated gluconeogenesis is an important marker in the evaluation of type II diabetes, mechanisms that are involved in PCK1  regulation have been extensively studied. One such study showed that the activation of PCK1 transcription has been shown to be controlled by histone deacetylases (HDACs) on different levels (Ref.) Note that HDAC is another well know potential target in cancer (Ref.1, Ref.2) sometimes addressed with the re purposed drug Valproic Acid (Ref.), and it is interesting to find here the connection of HDAC  with cancer also through PEPCK .

Another important connection in cancer related to gluconeogenesis has been revealed recently when it has been demonstrated that tumor suppressor p53 down-regulates the gluconeogenic key enzyme phosphoenolpyruvate carboxykinase (PCK1) (Ref.)

PEPCK and its inhibition has also been associated to the tumor inhibition in relation to cytoplasmic NADH build-up: “Proliferating cells must generate lipids and nucleotides, and to do so typically drive glycolysis at a high rate. This leads to a build-up of NADH in the cytoplasm which must be cleared for glycolysis to continue. The glycerol-3-phosphate shuttle is an important sink for NADH that could be significant for the growth of brat tumors. When there is not enough glycerol-3-phosphate  produced by glycolysis it is generated by another pathway called glyceroneogenesis. PEPCK is the main regulator for this pathway, and thus a significant contributor to the generation of glycerol-3-phosphate (see Figure)” (Ref.).

Note that glyceroneogenesis requires as a fuel various substances including Glutamine. Reducing an increased glyceroneogenesis that demands more Glutamine from the body, should add additional value in fighting cachexia as well.

Therefore, PEPCK plays an important role in major processes during tumor evolution.

It has been indeed demonstrated, that under glucose shortage PEPCK enzyme becomes activated, playing an important role in tumor adaptation to glucose shortage (Ref.1, Ref. 2). In this context, PEPCK role in cancer has been studied extensively (Ref.1, Ref.2). Here is an overview of the PEK1 activation in various cancer types: https://www.proteinatlas.org/ENSG00000124253-PCK1/pathology And here is an overview on the PEK2 activation in various cancer types: https://www.proteinatlas.org/ENSG00000100889-PCK2/pathology

Now, that we have seen the importance of gluconeogenesis and its key enzyme PEPCK in cancer, the questions is what are the tools available to inhibit PEPCK?

PEPCK inhibitors to inhibit gluconeogenesis

Here is a list of various substances known to be able to inhibit PEPCK:

  • 3-mercaptopicolinic acid (MPA), a drug that is the most known inhibitor for PEPCK (Ref.1, Ref.2)
  • Hydrazine is a drug often discussed in the alternative cancer treatment world, and it is a PEPCK inhibitor
    • Here is a recent Nature paper demonstrating the anti cancer potential (Ref.)
  • Metformin – indirect inhibition of PEPCK via
    • AMP-activated protein kinase (AMPK) activation – an enzyme that plays an important role in insulin signaling, whole body energy balance and the metabolism of glucose and fats – its activation reduces hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase (Ref.) AMPK is a central cellular energy sensor coordinating anabolic and catabolic pathways. AMPK limits energy consuming anabolic processes, like gluconeogenesis, and facilitates catabolic pathways (Ref.1, Ref.2)
    • inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP)
  • GSK-3 inhibitors can reduce the expression of gluconeogenic genes  (Ref.) Here is a paper on GSK-3 inhibitors (Ref.)

Hydrazine: a gluconeogenis (and glyceroneogenesis) inhibitor with anti tumor and anti cachexia potential

Hydrazine inhibits PEPCK (Ref.1,) and it is an inexpensive chemical which is commercially available. Hydrazine sulfate has been studied as an antitumor/antichachexia agent associated with cancer by Dr. Joseph Gold since 1970’s (Ref.). Dr. Joseph Gold, a medical doctor suggested that a metabolic circuit exists in cancer patients that allows energy required for tumor growth to be taken from normal metabolic processes in the human body. He suggested, lactic acid from tumor fermentation, amino acids from protein breakdown and glycerol from fat fuel gluconeogenic activity which drains away the energy which normal body processes need to produce and maintain tissue integrity. In turn, this causes cachexia in cancer. In his view, if the circuit could be broken, cachexia would be overcome and the cancer would he deprived of the energy needed to grow.

Hydrazine has been discussed extensively on the web and thus I will not address every point again.

For an extended discussion on Hydrazine, it’s anti cancer potential but also it’s possible side effects, please read these articles:

In line with the above discussion on the relevance of PEPCK, if Hydrazine would act as proposed by Dr. Joseph Gold, this substance would have the potential to

  • reduce gluconeogenesis leading to
    • stop cachexia
    • stop tumor evolution by
      • reduce blood glucose level that fuels tumors
      • reduce the capability of tumors to use lactate as a fuel for growth
      • reduce the lipid production inside the tumor cells, that is required for cellular division (Ref.)

Therefore, the use of Hydrazine could lead to the relief of heavy common symptoms related to cachexia found in cancer patients, and would additionally lead to tumor shrinkage via cancer cell starvation.

Indeed, there is a good amount of scientific literature, including clinical trials in humans, suggesting the important potential of Hydrazine:

In addition, here is a Nature paper published in 2017 showing that Hydrazine can indeed stop tumor growth https://www.nature.com/articles/s41598-017-11613-2

Regarding the administration protocol, according to this article, “Hydrazine sulfate is usually administered orally, with food or immediately before eating. It may also be given by injection. The usual cycle of treatment is 60 mg 3 times daily for 30–45 days followed by a rest period of 2–6 weeks. The cycle can be repeated as many times as desired. Each 60-mg dose is available in capsule form or in 15-mL vials for injection.” (Ref.). The same article discusses the safety aspects related to Hydrazine.

The administration protocol and related warnings are also very nicely addressed on this website: https://www.cancertutor.com/hydrazine/

Hydrazine sulfate is widely available, including on e-bay https://www.ebay.com/sch/i.html?_nkw=hydrazine+sulfate&ul_noapp=true. However, since it is cheap if I would like to use it I would better order it from large chemical suppliers such as this one https://www.scbt.com/scbt/product/hydrazine-sulfate-10034-93-2 – we never know what we order from small and unknown suppliers, so I would be very careful with that.

Conclusion:

Gluconeogenesis is a mechanism that needs to be addressed specifically in advanced cancer patients that are seeing fast loss of body mass.

One major way to reduce Gluconeogenesis is via oral administration of Hydrazine. This is a tool with great potential. However, since it has also some potential side effects, I would only use it in emergency case, when wight loss is present and can not be inhibited in any other way .

When I find time, I will search for other Gluconeogenesis/PEPCK inhibitors that have less or no side effects.

References:

The central role of hypothalamic inflammation in the acute illness response and cachexia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872506/

STAT3 in the Systemic Inflammation of Cancer Cachexia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867234/

The Surprising Truth About IGF-1 and How to Increase and Inhibit It https://selfhacked.com/blog/the-truth-about-igf-1-top-10-benefits-and-potential-drawbacks/

Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity – glucagon promotes (and insulin inhibits) cAMP-dependent mechanisms that down-regulate lipogenic enzymes and cholesterol synthesis, while up-regulating hepatic LDL receptors and production of the IGF-I antagonist IGFBP-1 https://www.ncbi.nlm.nih.gov/pubmed/10687887

If the insulin resistant state can increase cancer, then it stands to reason that treatments that enhance insulin sensitivity, such as caloric restriction, could improve cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595327/

Cellular and molecular mechanisms of metformin: an overview https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398862/

Sterol Regulatory Element Binding Proteins (SREBPs): Key Regulators of Nutritional Homeostasis and Insulin Action http://www.jbc.org/content/early/2000/08/08/jbc.R000017200.full.pdf

Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640658/

Gold J. Metabolic profiles in human solid tumors. I. A new technic for the utilization of human solid tumors in cancer research and its application to the anerobic glycolysis of isologous benign and malignant colon tissues. Cancer Res. 1966 Apr;26(4):695–705. [PubMed]

Gold J. Proposed treatment of cancer by inhibition of gluconeogenesis. Oncology. 1968;22(2):185–207. [PubMed]

Ray PD, Foster DO, Lardy HA. Paths of carbon in gluconeogenesis and lipogenesis. IV. Inhibition by L-tryptophan of hepatic gluconeogenesis at the level of phosphoenolpyruvate formation. J Biol Chem. 1966 Sep 10;241(17):3904–3908. [PubMed]

Gold J. Inhibition of Walker 256 intramuscular carcinoma in rats by administration of L-tryptophan. Oncology. 1970;24(4):291–303. [PubMed]

Ray PD, Hanson RL, Lardy HA. Inhibition by hydrazine of gluconeogenesis in the rat. J Biol Chem. 1970 Feb 25;245(4):690–696. [PubMed]

Gold J. Inhibition of gluconeogenesis at the phosphoenolpyruvate carboxykinase and pyruvate carboxylase reactions, as a means of cancer chemotherapy. Oncology. 1974;29(1):74–89. [PubMed]

Gold J. Inhibition of Walker 256 intramuscular carcinoma in rats by administration of hydrazine sulfate. Oncology. 1971;25(1):66–71. [PubMed]

Gold J. Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology. 1975;32(1):1–10.[PubMed]

Gold J. Anabolic profiles in late-stage cancer patients responsive to hydrazine sulfate. Nutr Cancer. 1981;3(1):13–19. [PubMed]

Chlebowski RT, Bulcavage L, Grosvenor M, Oktay E, Block JB, Chlebowski JS, Ali I, Elashoff R. Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer. J Clin Oncol. 1990 Jan;8(1):9–15. [PubMed]

Gold J. Enhancement by hydrazine sulfate of antitumor effectiveness of cytoxan, mitomycin C, methotrexate and bleomycin, in walker 256 carcinosarcoma in rats. Oncology. 1975;31(1):44–53.[PubMed]

Chlebowski RT, Heber D, Richardson B, Block JB. Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res. 1984 Feb;44(2):857–861.[PubMed]

Tweedie DJ, Erikson JM, Prough RA. Metabolism of hydrazine anti-cancer agents. Pharmacol Ther. 1987;34(1):111–127. [PubMed]

Stress and Glucose metabolism: A Review https://www.peertechz.com/articles/stress-and-glucose-metabolism-a-review.pdf

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This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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7 Comments on "Gluconeogenesis & How Hydrazine Could Help Fight Cancer and Cachexia"

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anca
Member

Hi Daniel and “Happy 2018!” to everyone,

Very interesting article, I think hydrazine is of real benefit for peaople in advanced stage cancer. Unfortunately mu mother could only use it for one month becasue she has a wound in the stomach and in the esophagus. She could die beacuse of the big ewound, because she had bleedin, she couldnt eat anything for almost 2 months, only tea and grape compote. Now I see some improvement, my mother could eat fish and potatoes in the morning, she is walking alone. But she still vomits. I hope she will be better, but we stopped every cancer treatment and every pills in November.

I wish everyone good health and the best results in treating their cancer,
Kind regards,
Anca

Jcancom
Member

Anca, a large insight into cancer has been gained on the Vitamin C thread.

iv dosing of Vitamin C at 1 g per hour for 10 hours per day with 5 days of dosing per week has significant anticancer effects.

The results were published in 1974 (see url below). The reason why this has not been clear for almost 50 years is that
current dosing schedules only dose for an hour or two (at up to 1 gram per minute not 1 gram per hour)
http://www4.dr-rath-foundation.org/NHC/studien_pdf/old/the_orthomolecular_treatment_of_cancer.pdf

Duration not dose is what is important. Vitamin C cuts off the energy supply to cancer. Cutting off the energy over a period
of only a few hours as occurs today has been shown to be almost entirely ineffective. Cancer can wait it out for a few hours.
However, it was found that cancer is unable to wait it out for many many hours. With prolonged Vitamin C dosing, cancer cells
are unable to cope. The great part with metabolic medicine is that there is no obvious path for cancer cells to develop resistance to
such a treatment; importing glucose to all cells is close to a universal requirement.

There are many ways that have been found to amplify the treatment effects of the basic 1974 protocol (i.e., 1 gram per hour for 10 hours for a 10 day cycle. Even still, this original protocol already had substantial responses.

Using this dosing approach could be of great help to your mother, though one risk to be aware of is TLS (i.e.,you would need to
manage the risk of the treatment being too effective). An added bonus of this treatment is that most of the patients treated
at 10 grams iv per 10 days at a minimum quickly derived symptomatic benefit.

Best Wishes to you and your mom in 2018.

Alex
Member

My mother’s situation is extremely dramatic.
I am asking for the fastest way to get actual Hydrazine Sulfate, in pill form to hopefully give my mother in time. And maybe, see some result, a good one.
Someone please help, i need it as fast as possible, before she doesn’t have a brain seizure.
Thank you very much, Alex