From Cancer to CoronaVirus: Therapeutic Strategy Based on the Similarities Between Cancer and Virus-Infected Cells

Introduction

(by Daniel Stanciu, PhD)

Dear Friends,

Since recently, there is a new section of this website entitled “Views in Oncology“, where invited guests are sharing with the world valuable information on cancer treatments. The invited guest is typically a professional from the academic- or clinical-space that positively stands out in his/her field of expertise or he/she has to share with us a new treatment perspective related to the oncology field, relevant for our goal to improve and extend life of cancer patients.

In this post, our Invited Guest is Dr. Andrey Glinka, scientist at the Division of Molecular Embryology, DKFZ-ZMBH Allianz, German Cancer Research Center, Heidelberg, D-69120 Germany. Relevant to note, DKFZ  is the national and the largest cancer centre of Germany (Ref.). This is the centre from where a lot of the great research results have emerged, that we often discussed on this website during the past years.

One scientific paper that I find outstanding in the research of Dr. Andrey Glinka and colleagues, was published during 2018 in the journal Cell Discovery. In this paper, the authors demonstrated that forced acidification of cancer cells using drugs such as Metformin can in turn induce inhibition of a key signalling pathway in cancer (called Wnt/β-catenin) (Ref.) and depleted cellular energy, decreasing stemness and viability of cancer cells. With the discussion below, Dr. Andrey Glinka goes one step further and ads here a contribution of important value due to two major reason:

  • it highlights the similarity between cancer and viral-affected cells – there is such a large overlap between the two that often makes us think that cancer looks a lot like an infectious disease
  • it provides a novel concept of a therapeutic strategy that is not only relevant to cancer but also to viral infections such as coronavirus, which currently represents a major health challenge

Therapeutic strategy based on the similarities between cancer and virus-infected cells

(by Andrey Glinka, PhD)
Division of Molecular Embryology, DKFZ-ZMBH Allianz, German Cancer Research Center, Heidelberg, D-69120 Germany

I would like to propose an additional strategy for our cancer drugs to be used in the treatment/prevention of viral infections, with a special focus on the current coronavirus epidemic (2019-nCoV).

There is a striking similarity between cancer cells and virus-infected cells in that both undergo a metabolic shift from oxidative phosphorylation to glycolysis, otherwise known as the Warburg effect.  As a result of the Warburg effect, which lowers intracellular pH (pHi) due to lactic acid accumulation, both cell types must invest heavily in exporting lactic acid to maintain correct pHi, which is essential for maintaining an increased cell cycle rate (cancer cells) and for assembling new viruses (virus-infected cells). Another common feature of both cell types is that they rely on fatty acid synthesis (Ref.) to enhance lipid production for proliferation (cancer) or for envelope assembly (virus).

Coronaviruses are assembled from RNA and viral proteins in the endoplasmic reticulum Golgi intermediate compartment (Ref.). During their assembly, viral proteins are highly sensitive to changes in intracellular ion composition, a distinctive feature that can be targeted with selective Ionophore drugs.  For example, the K/Na/H+ ionophore Monensin, which alters the correct balance of ions, can lead to defective modifications of essential coronavirus proteins (e.g. glycoproteins E1 and E2, Ref.). Moreover, one of the most critical parameters for the assembly of different types of viruses is intracellular pH, and it is possible that by lowering pHi with specific drugs, one can effectively interfere with virus amplification cycles. The following forum contains a list of many drugs that are capable of lowering pHi: (https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/).

One of the pHi-lowering drugs on the list is Metformin, which functions as a Mitochondrial complex I inhibitor. In a past publication (Ref.) we demonstrated that Metformin was able to decrease pHi specifically in cancer cells, with no effect on normal cells. In fact, all of the tested Mitochondrial Complex I inhibitors were found to have this effect. By analyzing tumors obtained from subset of lung cancer patients we have found that Metformin has a strong therapeutic effect on lung tissue – an organ that is heavily infected by coronaviruses. Furthermore, Metformin has also been shown to effectively target some virus-infected cells (Ref.). Hence, the application of Metformin in therapeutic doses may allow us to effectively treat the lungs of patients infected with coronaviruses. In order to test this hypothesis, an appropriate epidemiological study would need to be conducted. This would involve comparing the percentage of Metformin-receiving patients in a population infected with the novel coronavirus (2019-nCoV) against the percentage of Metformin-receiving patients in a local non-infected population of a similar age (see also Ref.). If a promising virus-lowering effect would indeed be detected in Metformin-receiving patients, this cheap and readily available drug could be provided as preventive or therapeutic medication in 2019-nCoV- struck China.

A second important drug worth investigating is Fenofibrate, which has long been used in humans as a lipid-lowering drug. Fenofibrate is also a Mitochondrial complex I inhibitor, but has the additional effect of interfering with lipid production, which is necessary for both cancer cells and viruses. We have previously demonstrated that Fenofibrate treatment cooperated with Metformin and Monensin in killing cancer cells (see also patent application (Ref.)). In addition, Fenofibrate alone was found to be active against viral infections (mouse model Ref.). Importantly, Fenofibrate can be given to patients combined with Metformin without any side effects (Ref.).

The third important drug on our list is Monensin, which belongs to the class of K/Na/H+ ionophores. Monensin also interferes with the amplification cycle of coronaviruses. In our study, we found that the combination of Metformin, Fenofibrate and Monensin produced a stronger effect on cancer cells when compared to single or double combination treatments (our patent application 2019). This triple drug combination caused strong intracellular acidification through the induction of a self-catalyzing cycle, an effect dubbed as the “Warburg Trap” (Ref.). Monensin has only been tested in animals and is widely used in agriculture.

To test the validity of our forced intracellular acidification approach on patients infected with 2019-nCoV, epidemiological data on Metformin use in infected vs. non-infected populations would, therefore, be decisive.

Disclaimer

Disclaimer here: https://www.cancertreatmentsresearch.com/?page_id=1794    

Related Articles


38 thoughts on “From Cancer to CoronaVirus: Therapeutic Strategy Based on the Similarities Between Cancer and Virus-Infected Cells

  1. Dear Andrey,

    Thank you again for your short, clear, great idea that at the same time it is easy to be applied. I hope many will understand the value behind this concept. And I hope visitors of this website will be kind enough to share this post via the social media channels as this information may actually save life if it works. And it is easy to check that.

    I do have a question here: Could we consider replacing Monensin with Salinomycin? Would you expect any major difference between the activities of the two in this combo? I am asking this question, because Salinomycin has been already applied in humans and the toxicity is known, while I am not sure if that is the case for Monensin. This is why, I gues it would be easier to use Salinomycin instead of Monensin.

    Thanks in advance for your response.

    Kind regards,
    Daniel

    1. Dear Daniel,
      I have tried in in vitro experiments Salinomycin and results are in our publication. Indeed, it could substitute Monensin. It requires 2 – 4 times higher concentration compare to Monensin to obtain same effects on cancer cells. Disadvantage of Salinomycin is low solubility, in original paper it was given to patients as intravenous injections in carrier containing high ethanol concentration. In animals, Monensin is safe oral drug – tested in many animals including monkeys.
      Andrey

      1. Hi Andrey,

        Thank you for your answer. Very helpful! This triggers a few more questions:
        1. Is there a specific reason you are aware of why Salinomycin has to be used in higher dose in order to be as effective as Monensin? Is it related to it’s capability to act as a ionophore?
        2. The base version of Salinomycin is indeed hardly soluble so we need to use both ethanol and a castor oil like formulation, but have you ever tried in the lab Salinomycin Salt, which is water soluble? Or would you expect that not to have similar activity for a specific reason?
        3. Regarding Fenofibrate: Once taken by humans, Fenofibrate rapidly becomes fenofibric acid. Would that have same effect at the cellular level? I remember prof Lampidis was combining it with 2DG, focused on ER stress, and he said there is a challenge related to the metabolism of Fenofibrate. If there is such a challenge in humans vs lab, would it make sense to change Fenofibrate with one or more drugs that would target same mechanisms?
        Thanks in advance for your view. I can imagine that some questions may be too detailed and please skip if you do not find them relevant.

        Kind regards,
        Daniel

        1. Dear Daniel,
          1,2 – I do not know specific reason for slightly better effect of Monensin in comparison to Salinomycin. Both were used in my experiments as sodium salts.
          3 – Fenofibrate is a fibric acid derivative, a prodrug that delivers fenofibric acid in cells. Fenofibric acid is an active form that reduces plasma triglycerides. It was found that Fenofibrate has aslo a property of mitochondrial complex I inhibitor. Important to note that fenofibric acid does not have this property (PMID: 25332241). Medical use of Fenofibrate suggests that there is a time window before decomposition to produce therapeutically relevant effect. Decreasing pHi in our experiments was obtained by fenofibrate. Fenofibric acid was not active.
          Regards,
          Andrey

          1. Hi Andrey,

            Thanks a lot for your clear and fair response! It’s very much appreciated.
            1. Great to know that you used the Salinomycin sodium salt in your experiment. That means that there is no reason we should think sodium salt version would not reach the same purpose, i.e. as a ionophore.
            2. I just came across a paper discussing the relevance of some antihistamine in cancer (AML) and the issue there was also the fast metabolism. As a result, the authors proposed to use liposomal versions. I think this could be a good idea for Fenofibrate application to increase the time window.

            Kind regards,
            Daniel

  2. Indeed fascinating research and explanation. If the right dataset appears the small chance is that Metformin can be used directly to treat new coronavirus.
    Would it be helpful to compare similar samples (age/gender etc.) of infected population who take Metformin (sample 1) and do not take Metformin (sample 2) additionally to what described in the article – percentage of Metformin taking among infected vs. non-infected?
    If only such data could be collected and made available by responsible officials…

      1. Dear Andrey,
        Thank you for response – this gives hope. I was wondering – does it make a huge difference to analyze available data which has diagnosis with different types of coronavirus cases (previous years), treatment with Metformin and outcomes?
        E.g. there are formalities but using e.g. they offer “SEER-Medicare: Outcome and Assessment Information set” for 260$ to cover preparation effort.
        Ivan

      2. Dr. Glinka, would you please share the recommended dosages for each drug? based on previous readings I assume Metformin could be taken up to 2 Grams if necessary. what about Fenofibrate and Monensin?

        1. Hi Pouya,

          I do not think that there is much information on toxicity of Monensin in humans to make a clear statement. But looking through the literature, my conclusion it is that is similar to Salinomycin, i.e. above >5mg/kg is the lethal rage, around 1mg/kg can be very dangerous and put people in the hospital for weeks/months, and probably around 0.2mg/kg is safe.

          Here are two articles describing cases of humans who ingested high amounts of Monensin, leading to their death:
          http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2001000400022
          https://www.ajkd.org/article/S0272-6386(01)13354-8/fulltext

          And here is a case of a man who survived after taking 4.6mg/kg Monensin:
          https://europepmc.org/article/med/28516409
          According to this the patient ingested an estimated 100 mg of monensin, followed by an additional 200 mg the following day. “Within hours after the second dose, the patient developed vomiting and abdominal pain and, over several days, began to experience significant leg pain, generalized weakness, and decreased urine output.”

          The same story we’ve seen with Salinomycin where people ingesting by mistake doses in the range of 1mg/kg developed significant side effects. On the other hand we also saw that when salinomycin is used in the safe range (about 0.2mg/kg) it may save or extend life of cancer patients.

          Kind regards,
          Daniel

          1. Hi D, thanks a lot. I understand that based on your previous comments it makes much more sense to take Sal instead of Monensin but I was thinking the salt version which is recommended is known to be expensive and that it might be easier to obtain Monensin here in Iran depending on which one is more popular in veterinary (haven’t looked into it yet, just an assumption) So I thought I would ask.
            as you probably have heard, Iran is quickly becoming the second most affected country after China due to government’s predictable incompetency in controlling the outbreak. it’s just people trying to save themselves now.
            I hope the Metformin-Fenofibrate combo would yield positive results too as Ionophores are hard to obtain and also not an easy treatment to apply for the average person.

            1. Dear Pouya,

              I am so sorry to hear that Iran is so strongly affected by coronavirus …

              If i would try to put together a cocktail against corona, having in mind
              – the article above, and
              – the fact that virus infection often disturbs endoplasmic reticulum (ER) homeostasis and leads to ER stress
              – the fact that ER stress up regulates glycolisis and lipogenesis,

              I would focus on the following:
              1. further increasing ER stress
              2. inhibiting lipogenesis
              3. inhibiting mitochondria
              4. inhibiting glycolisis
              5. acidifying the infected cells (which further increase the ER stress)

              1. Further increasing the ER stress can be done with
              – preferably antipsyhotic drug Pimozide https://www.cancertreatmentsresearch.com/community/pancreatic-cancer/recent-patent-on-combination-of-antagonists-of-dopamine-receptors-glycolysis-inhibitor-and-a-cholesterol-lowering-agent-to-inhibit-the-growth-of-pancreatic-cells/
              – and 2DG
              2. Inhibiting lipogenesis can be done with
              – preferably Atorvastatin
              – or Fenofibrate but it needs to be in liposomal formulation to be active
              – and other drugs such as discussed here https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/
              3. Inhibiting mitochondria can be done with
              – preferably Metformin
              – but I would also add Atorvaquone
              – and here are more such drugs https://www.cancertreatmentsresearch.com/a-list-of-mitochondria-inhibitors/
              4. Inhibiting Glycolisis can be done with
              – preferably Ritonavir
              – or 2DG
              – or other drugs such as https://www.cancertreatmentsresearch.com/drugs-and-supplements-that-block-fermentation-and-help-fight-cancer/
              5. Acidifying the infected cells can be done with drugs such as
              – Salinomycin (even the salt version) but if this is not available,
              – Amiloride and,
              – Acetozolamide and
              – Lanzoprazole and
              – Syrosingopine or Quercetin high dose
              – or other drugs mentioned here https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/

              So, combining Pimozide, Atorvastatin, 2DG, Metformin, Atorvaqone, Ritonavir, Amiloride, Acetozolamide, Lanzoprazole and Syrosingopine or Quercetin high dose, should build a strong antiviral cocktail.

              Kind regards,
              Daniel

        2. Dear Pouya,
          Metformin in combination with Fenofibrate:
          Metformin 500 mg orally three times daily, Fenofibrate – 200 mg orally once daily, (ref. https://www.ncbi.nlm.nih.gov/pubmed/22117989). I would believe that Fenofibrate could be also given in 3 doses. Maximal for fenofibrate would be 3 times 100 mg daily, (ref. https://www.amjmed.com/article/0002-9343(87)90867-9/pdf).
          Monensin: no therapeutically relevant data exist for humans. In our in vitro experiments maximal effect in cooperation with Metformin or Fenofibrate was obtained already at concentration of Monensin equal 5 nM, (300 000 times less molar concentration compare to Metformin, 2000 times less as Fenofibrate). This suggests that Monensin could to be given at very low doses. One could start from doses less then 1 mg 3 times daily. This should be done under professional medical control. Most expected dangerous side effect could be Rhabdomyolysis (ref. https://www.webmd.com/a-to-z-guides/rhabdomyolysis-symptoms-causes-treatments#1-3). There are well known symptoms of Rhabdomyolysis and also possibility to make blood test for Creatine kinase to detect onset of this illness in advance and subsequently decrease Monensin dose.
          Regards, Andrey

  3. thank you so much D. for Ritonavir I have contacted the friend I have in the UN as they are the only source to supply it in this country. not sure it will be available either but I’ll try. let’s see how it goes. things are getting ugly in Iran. authorities are stating fake numbers and the baffling part is that death rates of COVID-19 in Iran don’t match China’s. it is at least 3 times higher for some reason.

  4. so. so far I’m aware that in Iran the standard protocol to treat patients based on their condition is like this:
    for hospitalized patients with stable condition:
    Oseltamivir 75 mg for 5 days
    Hydroxychloroquine 200 mg
    Lopinavir/Ritonavir 50/200 mg 5 days
    _______________
    for hospitalized patients with severe symptoms
    same as above plus Ribavirin 1200 mg (in 6 *200 doses)
    -I’m not sure if these treatments are exactly what patients actually get in practice but this is what hospitals are told to do.
    and I’m curious whether this protocol is what WHO dictates? if not,I would like to see how treatment protocols vary across the globe. could explain a few things.

  5. Some promising news about Covid-19 got published today (I already bought Plaquenil two days ago, and was waiting for this):
    In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). PMID: 32150618

      1. Interesting WHO answer to the UV related question
        https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public/myth-busters
        “Can an ultraviolet disinfection lamp kill the new coronavirus?
        UV lamps should not be used to sterilize hands or other areas of skin as UV radiation can cause skin irritation.”

        I understand that they do it against possible misinterpretation and misunderstanding, but are people stupid and only deserve truth given at shallow level. Other source says that:
        https://www.thestar.com.my/news/regional/2020/03/05/virus-sensitive-to-uv-light-and-heat
        “According to the guideline, indoor spaces should be disinfected with UV light with an intensity of over 1.5 watts per square metre. A UV lamp can disinfect objects within one metre for at least half an hour.
        Longer exposure to radiation is needed when the temperature indoors is below 20°C or above 40°C and relative humidity is over 60%.A room should be ventilated after UV disinfection, and people are suggested to enter the room half an hour later. — China”

      2. Recent statement from China and some “strange” news around coronavirus:
        http://www.xinhuanet.com/english/2020-03/12/c_138870367.htm
        “The peak of the current outbreak of novel coronavirus disease (COVID-19) in China is over”
        “Mi said the number of new cases in Wuhan, the epicenter in central China’s Hubei Province, has dropped to a single digit, with only eight cases reported on Wednesday.
        Only seven new cases were reported on the Chinese mainland outside Hubei, but six were imported from overseas.”

        Lijian Zhao (Spokesperson & Deputy Director General, Information Department, Foreign Ministry)
        https://twitter.com/zlj517/status/1238114622684585984
        “Some #influenza deaths were actually infected with #COVID-19, Robert Redfield from US #CDC admitted at the House of Representatives. US reported 34 million cases of influenza and 20,000 deaths. Please tell us how many are related to COVID-19?”
        https://twitter.com/zlj517/status/1238110160884625409
        “1/2 CDC Director Robert Redfield admitted some Americans who seemingly died from influenza were tested positive for novel #coronavirus in the posthumous diagnosis, during the House Oversight Committee Wednesday. #COVID19”
        https://twitter.com/zlj517/status/1238111898828066823
        “2/2 CDC was caught on the spot. When did patient zero begin in US? How many people are infected? What are the names of the hospitals? It might be US army who brought the epidemic to Wuhan. Be transparent! Make public your data! US owe us an explanation!”

        and few days ago someone at Reddit points to the article in Nature dated back to 2015:
        https://www.nature.com/news/engineered-bat-virus-stirs-debate-over-risky-research-1.18787
        “Engineered bat virus stirs debate over risky research”
        “An experiment that created a hybrid version of a bat coronavirus — one related to the virus that causes SARS (severe acute respiratory syndrome) — has triggered renewed debate over whether engineering lab variants of viruses with possible pandemic potential is worth the risks.
        In an article published in Nature Medicine1 on 9 November, scientists investigated a virus called SHC014, which is found in horseshoe bats in China. The researchers created a chimaeric virus, made up of a surface protein of SHC014 and the backbone of a SARS virus that had been adapted to grow in mice and to mimic human disease. The chimaera infected human airway cells — proving that the surface protein of SHC014 has the necessary structure to bind to a key receptor on the cells and to infect them. It also caused disease in mice, but did not kill them.
        Although almost all coronaviruses isolated from bats have not been able to bind to the key human receptor, SHC014 is not the first that can do so. In 2013, researchers reported this ability for the first time in a different coronavirus isolated from the same bat population2.”

  6. Hi Daniel et al. Have you discussed w Dr Drevs his view on whether the `melt holes in cell walls in acidic environments` with IV aspirin & IV diflu will be effective w Covid-19? Given the lactic acid fermentation in both cases it seems worth considering. I also seem to recall Dr Drevs saying something about a history of success with either iv diflu or iv aspirin with some lung-related disease (tuberculosis?).

    Here is a link about more generic coronaviruses where “Here we show that D, L-lysine acetylsalicylate + glycine sold as“Asprin i.v. 500mg®” (LASAG), which is an approved drug inter alia in the treatment of acute pain, migraine and fever, impairs propagation of different CoV including the highly-pathogenic MERS-CoV in vitro.

    https://www.longdom.org/open-access/d-llysine-acetylsalicylate–glycine-impairs-coronavirus-replication-jaa-1000151.pdf

    1. HI Jess, very nice to hear from you! Your question is very good and thank you for the point on Salycilates and Corona. The question would fit better on this post https://www.cancertreatmentsresearch.com/a-list-of-drugs-and-supplement-to-fight-coronavirus/ but fit’s here too since here we start our first discussions on Corona.
      Only once I was in contact with Dr. Drevs, shortly, some years ago I think. It’s so difficult to keep contact with everyone, so I did not had the chance to discuss this with him again.

      Kind regards,
      Daniel

Leave a Reply