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Increased Glucose Uptake of Viral-infected Cells Suggests 2-DG Could Be Effective in the Fight Against COVID-19

COVID-19 Coronavirus Infections Viruses

From PET scan results to molecular biology data, it has long been known that increased glucose metabolism is a common trait of cancerous cells. More recently, however, viral-infected cells have also been found to increase their glucose uptake. In both cases, using carbon tracer experiments and mass spectrometry, glucose has been shown to be the molecule that provides the building blocks required to make more cancer cells and viral particles, respectively.

As an analog of glucose, 2-DG (2-deoxy-D-glucose) becomes a possible candidate for COVID-19 treatment by exploiting its preferential uptake in infected cells. 2-DG has also been shown to have anti-inflammatory effects that may benefit COVID-19 patients, especially in the latter phase of their disease. In a preliminary experiment completed on March 20, 2020, in the UK before the lab was closed in the national lockdown, 2-DG lowered the viral load by 1-2 logs in avian coronavirus infected cells in vitro at 3 and 10 mM.

Another advantage of 2-DG is its ability to block the replication of a variety of viral types by a number of different mechanisms which include the following:

  • Incorporating falsely into the structure of the viral capsid (head), leading to attenuation of its ability to become a fully infectious virus
  • Interfering with normal glycoprotein folding in the endoplasmic reticulum (ER) leads to ER stress blocking viral replication by activating the unfolded protein response and shutting down protein synthesis
  • By inhibiting glycolysis, 2-DG shuts off the building blocks required for a virus to replicate

Until today, however, there was no reliable data on how 2-DG would affect COVID-19. Using what is known as “in silico molecular modeling” (a non-cellular method which predicts how a drug will bind to its target and therefore inhibit its function), it has been shown that the structure of 2-DG fits into several of the binding sites that allow COVID-19 to attach as well as to replicate once it gets into a cell.

This is the first published report that directly examines the COVID-19 sites that 2-DG could have significant anti-viral activity on. It predicts that 2-DG will interfere with viral pathogenesis by binding what is known as its protease as well as its endoribonuclease. Each of these sites is required for proper viral replication and infectivity.

Moreover, the authors show that the docking of 2-DG with the main protease 3CLpro and NSP15 endoribonuclease of COVID-19 is significantly better than that of the standard anti-viral drugs lopinavir and favipiravir.

This recent publication together with the anti-viral activity of 2-DG previously reported in a number of different virus types, as well as via a number of different mechanisms by which it inhibits viral replication, adds further support to the call for 2-DG to be tested against COVID-19 live virus. We are aware of several such experiments currently taking place around the world – watch this space for further updates!

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2-DG ResearchLampidis NewsMedical Research

Data Supporting 2-DG as a Possible Treatment for COVID-19

female scientist in a busy research lab

The following is a review of the literature and evidence supporting the anti-viral properties of 2-DG, lending further credence to our hypothesis that it can be used as a possible treatment for COVID-19. We are in the process of putting together an international team of experts from the scientific community to accelerate this important work, and have applied to several organizations for grants to fund this research.

To donate to this cause

Preliminary results: 1 experiment completed March 20, 2020 at The Pirbright Institute (UK) before lab closed in national lockdown, indicating 2-DG lowers viral load by 1-2 logs in avian coronavirus infected cells in vitro at 3 and 10 mM.

2-DG spray effective in blocking rhinovirus in vitro and an in vivo animal model. Gualdoni GA, et al, and Stöckl J. Proc Natl Acad Sci USA. Jul 24;115(30) (2018)

Triggering unfolded protein response by 2-deoxy-D-glucose inhibits porcine epidemic diarrhea virus propagation. Wang,Y, Li,JR, Sun, MX, Ni, B, Huan, C, Huang, L, Li, C, Fan, HJ, Ren, XF and Mao, X. Antiviral. Res. 2014 Jun 106:33-41, (2014)

Activation of the unfolded protein response by 2-deoxy-D-glucose inhibits Kaposi's sarcoma- associated herpes virus replication and gene expression. Leung HJ, Duran EM, Kurtoglu M, Andreansky S, Lampidis TJ, Mesri EA. Antimicrob Agents Chemother. 56(11):5794-803, (2012)

2-DG safe and well-tolerated in cancer patients treated with oral bolus once per day, for periods up to a year. Raez LE, et al, Lampidis TJ. Cancer Chemother Pharmacol. 71(2):523-30. (2013) Currently being used by > 20 stage 4 cancer patients delivered metronomically 1 gm/24-48 hr slow infusion (2x per week for 18 mths in 1 pt) with no serious side effects reported at this dose

Report that Kaposi's sarcoma herpes virus induces increased glucose metabolism in host infected cell, similar to what is known in tumor cells. This provides strong support for the selectivity of 2-DG to preferentially accumulate in viral-infected cells. Delgado, T., Carroll, P. A., Punjabi, A. S., Margineantu, D., et al. Proc. Natl. Acad. Sci. USA 107, 10696– 10701. (2010)

Under normoxia, 2-DG elicits cell death in select tumor types by interfering with N-linked glycosylation. Kurtoglu,M et al. Lampidis TJ. Mol Cancer Ther. 6(11):3049-58, (2007)

Anti-viral action of 2-DG in herpes simplex virus by altering glycoproteins required for penetration and infectivity. Spivak, JG, Prusof, WH, Tritton, TR Virology, 123 (1) 123-138, (1982)

2-DG blocks infectious Rous Sarcoma virus replication by 100 fold but total replication only 3 fold. Unglycosylated envelope protein accounts for non-infectious virion. Stohrer, R and Hunter, E J Virol. 1979 32(2): 412–419, (1979)

2-DG incorporates fraudulently into oligosaccharide chain mannose disrupting influenza viral glycoprotein capsid formation. Datema, R and Schwarz, R. T. Eur J Biochem 184,113-123 (1979)

2‐DG blocks infectious Semliki Forest virus production in chick embryo cells ivia interference with glycosylation of virus‐specific glycoproteins. Schmidt, M. F. G., Schwarz, R. T. & Scholtissek, C. Eur Biochem 49: 237, (1974)

PLEASE NOTE: As with any new treatment, safety is the first consideration and that’s exactly why FDA approved clinical trials start with a Phase I trial – to ensure safety in humans and to determine the maximum tolerated dose (MTD). So before we have people going out and using 2-DG as a possible treatment for COVID-19, we need to make sure it’s safe, using the steps that all drugs take in getting to the general public.

 

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2-DG Research

2-DG and Coronavirus?

Abstract 3d cells of human or animal. Science concept

We have been developing 2-deoxy-D-glucose (2-DG), an analog of glucose, as a non-toxic anti-cancer agent and in an FDA-approved Phase I clinical trial, found it to be safe in patients.

In the trial, 2-DG was used for its inhibitory effects on glycolysis, thereby shutting down increased glucose metabolism, a universal trait of many different cancer types. The shutdown of glycolysis produces energy stress on the cancer cell which provides a window of selectivity since tumor cells require more glucose than normal cells.

However, 2-DG also mimics another natural sugar, mannose, which produces another kind of stress in the cancer cell referred to as endoplasmic reticulum (ER) stress – inducing an unfolded protein response (UPR), that in turn shuts down further protein synthesis in order to alleviate this kind of stress.

Since many viruses use ER to become fully formed and infective, they have developed a means to overcome (circumvent) UPR-mediated blockage of protein synthesis, which allows them to be produced.

We reasoned that with pre- or simultaneous treatment of virally-infected cells with 2-DG, activating the UPR would shut down protein synthesis, thereby blocking viral replication. We have previously reported that our idea worked in a herpes virus known to cause cancer in AIDS patients. Subsequent publications showed that 2-DG blocks viruses that either cause lethal hemorrhagic fever in pigs or the common cold in humans.

In the latter report, investigators used a nasal spray of 2-DG to block rhinovirus replication in animal models. Since coronavirus causes similar symptoms, it would be important to test 2-DG spray in preclinical models of coronavirus. If it worked, 2-DG nasal spray could be used by humans to not only treat those infected by coronavirus, but as a prophylactic to block viral infection spread.

In this way, what is known as “herd immunity” could be achieved similar to what vaccines such as the polio vaccine have done to wipe out the disease by eliminating susceptible individuals thereby blocking further infectivity.

The dual activity of 2-DG of inhibiting glycolysis and modulating protein synthesis, offers the possibility of blocking viral replication by more than one mechanism. In the rhino virus model mentioned above, the investigators showed that inhibiting glycolysis is how 2-DG blocks viral replication. Remodeling of glucose metabolism toward a more glycolytic one is emerging as a common trait of virally-infected cells.

Similarly, cancer cells undergo a shift from oxidative phosphorylation to glycolysis in order to meet the demands of rapid growth (known as the "Warburg effect"). In other words, viruses, as well as cancer cells, use glucose not only as a vital energy source but also as the building block for further production, which has been demonstrated with carbon 13 tracer experiments and mass spectrometry.

Thus, by interfering with the increased glucose metabolism of virally-infected cells, 2-DG offers a possibility of using a proven, non-toxic, inexpensive and rapid means of treating viral outbreaks such as that of coronavirus.

Having 20+ years of experience in investigating the mechanisms by which 2-DG interferes with glucose metabolism, and interacting with investigators that are experts in herpes viral replication here at the University of Miami, and those developing 2-DG nasal spray for the common cold at the Vienna Medical Institute in Austria, and more recently with an expert in coronaviral replication in England, I believe we may have enough expertise to make an impact on this current world-wide pandemic.

Any resources that readers of this blog can contribute will be donated directly to this immediate cause.

PLEASE NOTE: As with any new treatment, safety is the first consideration and that’s exactly why FDA approved clinical trials start with a Phase I trial – to ensure safety in humans and to determine the maximum tolerated dose (MTD). So before we have people going out and using 2-DG as a possible treatment for COVID-19, we need to make sure it’s safe, using the steps that all drugs take in getting to the general public.

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2-DG Continues to Show Highly Promising Results in Late-stage Cancer Patients

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Since 2-DG became available in Germany in 2018, The Lampidis Cancer Foundation has been actively collaborating with participating doctors and clinics worldwide on implementing protocols for metronomic (slow-release) delivery of patient grade 2-DG for compassionate use cancer treatment to patients with highly promising preliminary results across different cancer types.

  • Patient A, female, 40-50 years, (Spain) – Stage 4, Endometrial Cancer: After intensive treatment where metronomic 2-DG was included, reduction of tumor markers from 240 to 80 and destruction of at least half of the 14 lung nodules were reported.
  • Patient B, femaie, 50 years, (Romania) – Stage 3, Ovarian Cancer: Advanced cancer with no treatment before beginning M2-DG. Accepted 10 X lower than normal chemotherapy (cisplatin + paclitaxel) with M2-DG and metformin. In complete remission.
  • Patient C, femaie, Glioblastoma (Spain): Patient’s condition has improved since using a combination of M2-DG + Salinomycin. The tumor is stable and showing signs of regression.

These remarkable, albeit anecdotal results are based on Dr Lampidis’ groundbreaking research using a false sugar (2-deoxy-D-glucose or 2-DG) to literally starve the treatment-resistant, slow replicating cancer cells found at the core of all tumors, which require glucose to survive in a non-oxygen (hypoxic) environment. In vivo and in vitro studies successfully demonstrated that 2-DG is able to kill the most resistant cancer cell populations found within every solid tumor, which led to the successful completion of a FDA-approved Phase 1 clinical trial. Subsequent experiments in the lab demonstrated that using a metronomic (slow-release) pump to deliver 2-DG at continual, low level doses avoids both an insulin response and liver absorption whilst increasing efficacy of significant tumor volume control. Although the preliminary clinical data from current human use studies is still at an anecdotal stage, it is encouraging to know that several patients receiving metronomic 2-DG treatment via pump through a central venous catheter (PICC line) are reporting excellent tolerance as well as a reduction in the size and/or elimination of their respective tumor types.

HOW YOU CAN HELP: We are currently lobbying the FDA to gain approval for metronomic 2-DG treatment to be administered in the US under the Right to Try Act.

If you are an oncologist or integrative medicine physician interested in using this treatment protocol on your patients, contact us here.

If you are a cancer patient or caregiver interested in learning more about this treatment protocol, contact us here.

 If you are interested in supporting our mission to deliver a low cost, non-toxic cancer treatment to millions of patients worldwide, donate here.

 

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Developing a Non-toxic Approach to Treating Cancer

Orange

Combining non-toxic glycolytic inhibitors with non-toxic antibiotics 

Although it has long been known that the anti-oxidant properties of vitamin C may be linked to its purported anti-cancer properties, more recently the blockage of glucose uptake by vitamin C appears to be another important anti-cancer property of this widely used and non-toxic agent.

Importantly, in this recent report published in Oncotarget, the investigators show that combining vitamin C with the widely used antibiotic, doxycycline, which affects mitochondrial function, yields potent toxic effects across a broad range of tumor types.

We have previously shown similar wide-reaching anti-cancer activity with the glycolytic inhibitor, 2-DG, when used in cancer cells that have their mitochondrial function compromised either by exposure to low oxygen (hypoxia), or when co-treated with a mitochondrial agent, or when harboring a genetic defect in their mitochondrial DNA.

Interestingly, in this latest report, the authors suggest vitamin C to be more potent than 2-DG when combined with doxycycline. It would appear, however, if this strategy is applied to humans, then the benefits of the known selective uptake of 2-DG in cancer versus normal surrounding tissue (supported by the results of millions of PET scans) would make 2-DG a more cancer-specific agent to combine with doxycycline than vitamin C.

Overall, this recent publication further supports the continued development and investigation of combinations and strategies aimed at how to best use 2-DG to exploit increased glucose uptake and metabolism, which is a universal trait of cancer.

Our groundbreaking cancer research relies largely on philanthropy to keep moving forward. Please consider donating to our cause. Our goal is to raise $300,000/year to conduct the necessary research to bring our 2-DG treatment protocol through the relevant clinical trials in order to make it available to patients worldwide. We would appreciate your help by donating using the link above.

 

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Further Evidence that 2-DG Inhibits Aggressive Breast Cancer Cells

Breast Cancer Detection and Treatment

In a recent publication titled 2-Deoxy-D-Glucose Inhibits Aggressive Triple-negative Breast Cancer Cells By Targeting Glycolysis And The Cancer Stem Cell Phenotype – a research group in Ireland, headed by Dr. Lorraine Driscoll, showed that triple-negative breast cancer (TNBC) cells which are particularly resistant to conventional treatment in patients are sensitive to 2-DG. The study compares a particularly aggressive strain of TNBC to its less aggressive parental type. It shows that the more aggressive strain has in vitro characteristics (migration, invasion, and resistance to anoikis – a form of programmed cell death) of being metastatic. Results indicate that all three of these metastatic traits can be inhibited by 2-DG based on differences in the metabolism of these two TNBC lines.

However, the doses of 2-DG used in these experiments are 7.5 to 15 times greater than what we have previously shown can be achieved in patients when taking 2-DG orally once per day. Moreover, if used in patients, the doses in this study are at concentration levels where liver adsorption, as well as insulin induction, would redirect 2-DG into liver, fat and muscle cells and away from tumor sites.

This further supports the use of metronomic 2-DG (i.e., delivered via a slow-release pump) as a viable means of delivering 2-DG at low enough doses that will not induce liver adsorption and/or induction of an insulin response. Based on the millions of PET scans conducted to date, it is known that low dose 2-DG does preferentially accumulate in tumor versus normal cells. These results are now explained by more recent findings demonstrating that the very genes that are driving cancer (oncogenes) are found to also be responsible for increased glucose uptake and metabolism, justifying labeling 2-DG as a universal treatment for cancer. Thus, continuous slow-infusion of 2-DG will effectively accumulate in tumor cells and eventually reach a concentration that will be preferentially toxic to cancer versus normal cells.

We are currently exploring opportunities with the US Food & Drug Administration to make our metronomic 2-DG treatment protocol available to Stage 3 and 4 cancer patients under the FDA’s “Compassionate Use” designation. Watch this space for further updates.

Our academic research relies largely on philanthropy to keep moving forward. Please consider donating to our cause. Our goal is to raise $300,000/year to provide the necessary research to bring our 2-DG treatment protocol through the relevant clinical trials in order to make it available to patients worldwide. We would appreciate your help by donating using the link above.

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More Patients Reporting Encouraging Results Using Metronomic 2-DG in Fight Against Cancer

Ethnic young adult female cancer patient sipping tea

As reported in September, the Lampidis Cancer Foundation, along with the MCS Foundation for Life, has been actively collaborating with clinics worldwide on implementing protocols using 2-DG for patients who have failed standard treatment. The following patient updates have been received as of the end of January.

  • Patient A, male, 25 years, Ewing Sarcoma (grade 3): Prior to and after surgery and radiation therapy, metronomic 2-DG was administered, and there has been no sign or evidence of recurrence. It has been applied with other metabolic treatments and oncothermia.
  • Patient B, female, Ovarian Cancer (stage 4 with spleen and liver metastasis, and ascites): Metronomic 2-DG was administered after each session of low-dose chemotherapy (IPT) for 2 months. After treatment, there has been no sign or evidence of recurrence.
  • Patient C, male, Maxillary Carcinoma (stage 4, multiple metastasis including the brain, liver, bones, eye): This patient could not maintain chemo (Capecitabine and Irinotecan) due to the side-effects and continuous growth of tumors. After administering metronomic 2-DG, he is improving while some tumors are shrinking, including those in the eye.

One of the physicians reporting on the first two patients commented: “Although I am currently unable to quantify the actual contribution of 2-DG to these results, I am convinced it is having a positive impact. Furthermore, these results are highly unusual, as inoperable pancreatic cancer and grade 3 sarcomas are extremely aggressive.”

Since these stage 3 and  4 patients are concurrently receiving other treatments in addition to 2-DG, the data must be considered anecdotal. Nevertheless, as this is the first time patients have been treated with our laboratory-tested delivery method, it is very encouraging to know that excellent tolerance as well as reductions in the size of their respective tumor types and markers is being reported.

We will continue to report on patient outcomes from around the world as we receive them.

Our academic research relies largely on philanthropy to keep moving forward. Please consider donating to our cause. Our goal is to raise $300,000/year to provide the necessary research to bring this treatment protocol through the relevant clinical trials in order to make it available to patients worldwide. We would appreciate your help by donating using the link above.

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2-DG Research

Controlling Ebola with 2-DG?

150203163641-ebola-virus-virion-outbreak2-super-169

Recently, we reported that the replication of herpes virus (KSHV) known to cause the most prevalent cancer in AIDS patients, can be inhibited by treatment with the dual glucose and mannose analog, 2-deoxy-D-glucose (2-DG). The mechanism we uncovered, which we believe could be applied to many viral types including Ebola, is explained as follows.

During the peak of viral replication, glycoproteins are mass produced in the endoplasmic reticulum (ER) – an intracellular organelle. This leads to ER stress which normally through an unfolded protein response (UPR) inhibits further protein synthesis in order to reduce the proteins entering the ER, thereby maintaining ER and cellular homeostasis. However, in order to replicate, viruses have acquired the ability to circumvent the UPR, thereby allowing the viral particles to be produced in the ER. We hypothesized that by applying clinically achievable non-toxic doses of 2-DG to viral-infected cells and inducing exogenous stimulation of ER stress, this would result in shutting down protein synthesis required for viral replication. Indeed, this is what we found in the lab and moreover demonstrated that “viral cascade genes” required for viral replication, including the master transactivator (RTA) gene, glycoprotein B, K8.1, as well as angiogenesis-regulating genes required for tumor growth, are markedly decreased with 2-DG treatment.

Overall, our results demonstrate that exogenous induction of ER stress by 2-DG provides a new means of inhibiting herpes viral replication and suggest that this strategy may be applicable to other viruses such as Ebola.

Since our report on this work published in 2012, another more recent trial using 2-DG to exogenously induce ER stress has been shown to be effective in blocking the replication of a porcine virus that affects pigs, resulting in massive destruction of these animals which are critical for the food supply in certain third world countries.

We would like to partner with any organization currently working to contain the deadly Ebola virus to accelerate this discovery, as our lab is not equipped to test this idea in an Ebola model.

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Latest 2-DG Breakthrough Raises Hope of Non-Toxic Cancer Treatment

cancer cell

New Study Shows That Combining 2-DG and Fenofibrate Kills a Wide Variety of Cancers
May 10, 2016, Miami, FL :: Dr. Theodore J. Lampidis, Professor of Cell Biology at the University of Miami Miller School of Medicine, today announced a major breakthrough that paves the way for a viable non-toxic treatment of a wide variety of cancers.
Dr. Lampidis is a pioneer in the exploration of glucose metabolism in cancer cells and the discovery of how to exploit this process by using simple sugars such as 2-Deoxy-D-glucose (2-DG). 2-DG has been found to inhibit glycolysis, which the most malignant cancer cells found in the inner core of all solid cancers rely on to survive. It is these cells that by nature of their slow growth are resistant to conventional cancer treatments such as radiation and chemotherapy, which are limited to attacking the rapidly dividing cells located in the outer part of a tumor.
Although a Phase 1 clinical trial proved that this strategy using 2-DG was successful, the toxic side-effects of chemotherapy remained an issue. However, this latest study, published today in Oncotarget, shows that by combining 2-DG with fenofibrate, a compound that has been safely used in humans for over 40 years to lower cholesterol and triglycerides, the entire tumor can effectively be targeted without the use of toxic chemotherapy.
“We found that the unique combination of 2-DG and fenofibrate simultaneously provokes two types of stress, known as energy and ER stress, which most of the cancer types tested cannot overcome,” according to Dr. Lampidis.
Due to uncontrolled growth and to the abnormal micro-environment in which cancer cells exist, they are under more stress than normal healthy cells. Thus, in addition to 2-DG taking advantage of the universal cancer trait of increased glucose uptake, adding fenofibrate effectively exploits a second common feature of cancers: increased stress.
Dr. Lampidis concludes: “We believe our findings effectively pave the way for using this combination to provide non-toxic treatments for a wide variety of cancers.”
Full article published here: http://www.genengnews.com/gen-news-highlights/non-toxic-method-for-treating-cancer-reportedly-developed/81252741

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