This is a glucose analog that is avidly taken up by cancer cells. DeoxyGlucose (2DG) differs from normal glucose only by removal of an oxygen atom from the hydroxyl group at the 2 position.
2DG is one of the most relevant glycolysis inhibitor. Since it is a glycolysis inhibitor, it is relevant to all cancers visible on PET scan. It has been already tested on humans in clinical trials, with promising anti cancer results. It is also patented by various parties as an anti cancer and anti viral substance (Ref.) However, it is a simple, safe and accessible substance.
In simple words, supplying cancer cells with 2DG (instead of glucose) is like putting water in the car tank instead of petrol. The cancer cells will take it up expecting that is glucose but instead 2DG is a form of glucose that it cannot be broken down like other sugars to generate energy, and thus effectively starving the cancer cells (Ref.).
I think that 2DG is a good addition to any anti cancer protocol (as long as the cancer is PET positive). If it doesn’t kill cancer at least it will reduce the energy of the cancer cells so that other treatments (including chemo therapy) can be more effective.
Update November 2018: Best is to use 2DG in a metronomic treatment strategy (Ref.)
Case reports & Clinical trials
Warburg science goes to the bedside: A phase I trial of 2-deoxyglucose in patients with prostate cancer and advanced malignancies http://ascopubs.org/doi/abs/10.1200/jco.2008.26.15_suppl.16087
Background: A profound, but therapeutically unexploited, difference between cancer and normal tissues is the preferential utilization of glycolysis (the ‘Warburg effect’) for energy by cancer cells. Additionally, similar to mechanisms of chemotherapy resistance, potential mechanisms of cancer cell resistance to starvation have recently emerged. One pathway by which cells survive periods of metabolic stress is thought to be autophagy, which is a catabolic process of organelle digestion that creates ATP during periods of nutrient limitation and is regulated by the protein Beclin1. Methods: We developed this novel paradigm in pre-clinical models and a phase I clinical trial. Preclinically, we used immortalized mouse epithelial prostate cells, as well as PC-3 and LNCaP cell lines, and a transfected pEGFP-LC3 autophagy marker construct to assess cytotoxicity and autophagy induction by 2-deoxyglucose (DG). In the clinic, eligible patients receive DG orally on days 1-14 of a 21 day cycle in cohorts of 3 in a dose escalating manner. Planned correlative assessments in patients included PET scans at baseline and day 2, as a p
otential marker of DG uptake, Beclin1 in initial tumor blocks, and LC3 protein in peripheral blood mononuclear cells as a potential marker of autophagy. Results: In preclinical models, we demonstrated cytotoxicity and induction of autophagy, which was dependent on Beclin1 expression. To establish methods for the clinical trial, we stained a human prostate TMA (>35 patients) for Beclin1 by IHC. In the clinical study, 6 patients have been treated at doses 30 and 45 mg/kg/day orally and a 3rd cohort is accruing currently at 60 mg/kg. Therapy was well tolerated with no dose-limiting toxicity. Of three patients with prostate cancer, one patient has received more than 11 cycles with a stable PSA for over 6 cycles. Of three patients in which PET was performed at baseline and follow-up, one patient had marked decrease in tumor site SUV and a second patient a minor decrease. Accrual is ongoing. Additional PET and assessment of LC3 and Beclin1 correlatives are ongoing. Conclusions: These initial data support the safety of DG and translational advancement of the rapidly developing paradigm of targeting the metabolic fragility of cancer.
TargetingTumor MetabolismWith 2-Deoxyglucose in Patients With Castrate-Resistant Prostate Cancer and Advanced Malignancies http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142700/
BACKGROUND: A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance.
METHODS: Patients received 2DG orally on days 1€“14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance.
RESULTS: The dose of 45 mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60 mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with Cmax 45 Î¼g/ml (277 Î¼M), 73.7 Î¼g/ml (449 Î¼M), and 122 Î¼g/ml (744 Î¼M) in dose levels 30, 45, and 60 mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24 hr.
CONCLUSIONS: These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy.
A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. http://www.ncbi.nlm.nih.gov/pubmed/23228990
PURPOSE: This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors.
METHODS: A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and docetaxel was administered intravenously at 30 mg/m(2) for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles.
RESULTS: Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel.
CONCLUSION: The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects.
2DG differs from normal glucose only by removal of an oxygen atom from the hydroxyl group at the 2 position . When provided exogenously, 2DG is taken up by glucose transporters and is subsequently converted to 2-deoxy-D-glucose 6-phosphate (2DG-6P), which cannot be converted to fructose-6-phosphate by phosphoglucose isomerase. This prevents metabolism through subsequent steps of glycolysis. The trapping of 2DG-6P in cells after uptake through glucose transporters has enabled the use of 2DG as a metabolic tracer for glucose utilization and its adaptation in positron emission tomography (PET) scanning using F- 2DG in clinical imaging. Ref This 2DG accumulation in cancer cells is inducing early blockage of glycolytic pathway, leading to the cancer cell death.
2DG is seen as an inhibitor of hexokinase (HK).
Many studies suggest that the toxicity of 2-DG can be attributed to the inhibition of glycosylation. (Ref.)
While it is a safe element at doses tested in clinical trials, higher doses may be toxic to the brain due to the typical high glucose consumption in the brain. Administration of 1g 2DG IV to 30 min may lead to headache.
QTc prolongation at higher dose was observed in clinical trials (Ref.)
Although I would not use such a high dose, it has been suggested that 200 mg/kg do not cause any serious adverse events, after its administration in IV form to 700 people (Ref.) Based on our experience this is highly debatable.
Patients on ketogenic diet are probably the most safe at high doses of 2DG since the brain will mainly rely on ketones.
Update January 2019: Indeed here is an article indicating that ketogenic diet can help: “Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet” (Ref.).
Propranolol, previously discussed on this website for its anticancer effects, can also help to inhibit the hyperglycemia triggered by high dose 2DG and mediated by catecholamine release (Ref.1, Ref.2). Indeed, there are many old reports indicating that glucose spikes happen following 2DG administration and these are a result of the increased secretion of noradrenalin from the hypothalamus leading to the release of glucagon from the pancreas, mobilization of fatty acids, breakdown of liver glycogen and gluconeogenesis https://
3. reduce the 2DG dose to a level that dose not trigger the glucose spike level
Preparation & Administration
From clinical trial: 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). http://www.ncbi.nlm.nih.gov/pubmed/23228990
It is a water soluble substance.
According to the above clinical trial, the dose of 63mg/kg is identified as clinically tolerable dose when administrated orally. This means that a person of 50 kg would need about 3g/day. However, assuming that we are using other drugs as well and not relying on 2DG only, I would go to doses higher than 2g/day only if there is nothing else left to use.
The administration will take place 7 days every other week and the 2DG powder is taken as capsules or if possible pre-mixed with some water.
Bolus IV delivery:
If on the other hand we wish to take the IV route than I would use 1g/IV administrated 1x/day at a frequency of 2-5x/week.
2DG for IV possible prep method:
– target dose is 1g 2DG
– take the 2DG powder as measured with a digital scale and add in a sterile (or very clean) cup/vial.
– mix the powder with 10ml sterile water or sterile saline
– when the solution is well mixed (i.e. no 2DG powder visible) take all the solution into a syringe
– take out the used needle and instead put a 0.2um sterile filter on the syringe – at the other side of the filter mount a new sterile needle.
– inject this 2DG solution into the 100ml NaCl (saline) bottle/bag
– administer this solution in about 1 hour (reduced administration to 30 min may lead to headache – indeed brain is the first affected by 2DG overdose since it is strongly depended on the glucose consumption – a patient on ketogenic diet will deal much better with fast 2DG administration)
This is just an idea of formulation.
Tools and Materials needed to prepare the IV 2DG solution:
– digital scale that measures 1mg
– 0.2um sterile filters for syringe
– glass vials to mix 2DG with saline, like this or similar
– Of course there is a need for all the typical stuff required for IV like saline (100ml), delivery kit, syringes, needles, water for injection.
Update August 2020: A new report on the safety of administration of intravenous 2DG in humans: Safety of Antimetabolite 2-Deoxy-D-arabinohexose (2DG) as a Coadjuvant Metabolic Intervention in 268 Cancer Patients
Metronomic IV delivery:
See the following post.
Update November 2018: Best use of 2DG is in a metronomic approach (Ref.) next to mitochondria inhibitors (Ref.) and authophagy inhibitors (Ref.), all as a basis to support conventional treatments such as chemo- and radio-therapy.
Source & Cost
CAS Number 154-17-6
It can be bought from Western or Chinese chemical suppliers http://www.sigmaaldrich.com/catalog/product/sigma/d8375?lang=en®ion=NL as powder and than it needs to be sterilized and prepared as discussed above.
It can also be found at compounding pharmacy prepared in the IV form.
It costs about 200-300$ for 50g at the Chinese suppliers and about 50 euro for 1g ready for IV (already mixed in an IV bag) at compounding pharmacy.
Synergies & Antagonists
It works in synergy with most of the anti cancer treatments regardless on whether those are conventional or alternative.
3BP & 2DG: According to the theory in which tumors behave as metabolic symbionts (see fig. 5 in Ref.) it may make sense to first treat the patient with 3BP to kill the oxygenated tumor cells and than apply 2DG to kill hypoxic tumors cells that rely on glycolysis for survival and proliferation.
Salinomycin & 2DG: It makes send to first treat patients with 2DG to lower the capabilities of cancer cells to resist Salinomycin, followed by Salinomycin IV
Metformin & 2DG: to inhibit both glycolisis and OXPHOS (Ref.)
“However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment.” (Ref)
Hydroxychloroquine & 2DG: EFFECT OF DUAL INHIBITION OF APOPTOSIS AND AUTOPHAGY IN PROSTATE CANCER Ref
It is actually indicated that all the metabolic treatments should be combined with autophagy inhibitors such as Chloroquine (Ref.). The potential of 2DG+autophagy inhibition is also discussed in this clinical trial.
Fenofibrate & 2DG: Combining 2-Deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=9263&path%5B%5D=28508
Update: Propranolol, discussed on this website for its anticancer effects, can also help to inhibit the hyperglycemia triggered by high dose 2DG and mediated by catecholamine release (Ref.1, Ref.2). In addition it has autophagy inhibition properties (Ref.) that makes it very relevant for combo with 2DG.
Clinics Treating Patients with 2DG
Because it is available at compounding pharmacy, many clinics may offer this treatment. Here is a clinic in Frankfurt that offers 2DG IV http://www.erweiterte-medizin.de/
Other relevant links:
Anticancer Targets in the Glycolytic Metabolism of Tumors: A Comprehensive Review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161244/
Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263/737 Combination Therapy http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176271/ The compound 2-deoxyglucose (2DG), in contrast, partially blocks glycolysis, slowing cell growth but rarely causing cell death. Injected into an animal, 2DG accumulates predominantly in tumors but does not harm other tissues.
Dual inhibition of Tumor Energy Pathway by 2-deoxy glucose and metformin Is Effective Against a Broad Spectrum of Preclinical Cancer Models http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237863/ A combined use of 2DG and AICAR also failed to induce cell death. However, 2DG and metformin led to significant cell death associated with decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy. Gene expression analysis and functional assays revealed that the selective AMPK agonist AICAR augments mitochondrial energy transduction (OXPHOS) while metformin compromises OXPHOS. Importantly, forced energy restoration with methylpyruvate reversed the cell death induced by 2DG and metformin, suggesting a critical role of energetic deprivation in the underlying mechanism of cell death. The combination of 2DG and metformin inhibited tumor growth in mouse xenograft models. Deprivation of tumor bioenergetics by dual inhibition of energy pathways might be an effective novel therapeutic approach for a broad spectrum of human tumors.
Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523878/
Paclitaxel Combined with Inhibitors of Glucose and Hydroperoxide Metabolism Enhances Breast Cancer Cell Killing Via H2O2-Mediated Oxidative Stress http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843822/
Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123079/
Glycolytic inhibition alters anaplastic thyroid carcinoma tumor metabolism and improves response to conventional chemotherapy and radiation http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856684/
Mitochondria targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700358/
TargetingTumor MetabolismWith 2-Deoxyglucose in Patients With Castrate-Resistant Prostate Cancer and Advanced Malignancies http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142700/
Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913946/
Antiangiogenic Activity of 2-Deoxy-D-Glucose http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965179/ In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies.
Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation http://www.nature.com/bjc/journal/v111/n1/full/bjc2014272a.html The most glycolytic pancreatic cancer cell line was exquisitely sensitive to 2-DG, whereas the least glycolytic pancreatic cancer cell was resistant to 2-DG. However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment.
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