ATP Depletion Therapy

Safe & Effective Complementary Cancer Treatment
Biochemical ATP Depletion Therapy Basics 
Biochemical ATP Depletion Therapy utilizes specific biochemical molecules and dietary supplements that were shown to inhibit the activity of the targeted enzymes that were highly overexpressed in cancer cell energy metabolism and contribute to the excessive ATP synthesis fueling the rapid and uncontrolled cell division.  
 
Biochemical ATP Depletion Therapy generally targets both the mitochondrial oxidative phoshorylation and glycolysis simultaneously as cancer cells often have the capability of switching between alternate ATP synthesis pathways when one of them is suppressed. The use of specific biochemicals/dietary supplements generally need to be accompanied by nutritional modifications for additional efficacy.
 
Due to the substantial differences in their energy metabolism compared to regular cells, it is possible to selectively target the ATP synthesis of cancer cells leading to their death without causing major side effects to the patients.
 
The selectivity of specific ATP depleting biochemicals against cancer cells can be understood in looking at the PET Scan image of a cancer patient in the picture. In PET Scan patients are given an injection of radio-labelled glucose analog 18FDG (18fluorodeoxyglucose) which accumulates in tumors as black spots because they are absorbed in much higher quantities by cancer cells. Like fluorodeoxyglucose, a smilar glucose mimetic deoxyglucose is also not metabolized and preferentially blocks glycolysis in cancer cells and is being tested in clinical trials as a glycolytic inhibitor.
 
ATP Depleting Biochemicals and Their Targets
ATP Depleting Biochemicals generally target either the mitochondrial oxidative phosphorylation or glycolysis where few of them may actually target both in cancer cells. Below you may find some selected biochemicals and their target sites or enzymes. Few studies showing their efficacy against tumors are provided in this page where abstracts and links to over 100 scientific articles can be accessed the Scientific Research section.
 
Active Substance
Alpha Tocopheryl Succinate           
Annonaceous Acetogenins              
Benzyl Isothiocyanate                    
3-Bromopyruvate                            
Delocalised Lipophilic Cations         
2-Deoxy-D-Glucose                       
Curcumin                                     
Dichloro Acetic Acid                     
Gossypol Acetic Acid                   
Hydroxycitric Acid                        
Koningic Acid                              
Lonidamine                                  
Methylglyoxal                               
Methyl Jasmonate                        
Nordihydroguaiaretic Acid             
Nonsteroidal Anti-Inflammatory Drugs       
SodiumOxamate 
Target Site or Enzyme
Mitochondrial Respiratory Complex II 
Hexokinase & Mitochondrial Respiratory Complex I
Mitochondrial Respiratory Complex III
Hexokinase
F0F1-ATPase and/or NADH-Ubiquinone Reductase
Phosphohexose Isomerase
Glyceraldehyde 3-Phosphate Dehydrogenase & Glyoxalase
Pyruvate Dehydrogenase Kinase
Lactate Dehydrogenase-X
ATP Citrate Lyase
Glyceraldehyde 3-Phosphate Dehydrogenase
Hexokinase
Mitochondrial Respiratory Complex I & Glyceraldehyde 3-Phosphate Dehydrogenase
Mitochondrial Permeability Transition Pore Complex & Hexokinase
Mitochondrial Respiratory Complex I
Oxidative Phosphorylation Uncouplers
Lactate Dehydrogenase-A 
 
 
Effect of Biochemical ATP Depletion on Cancer Cells  
When the ATP synthesis in inhibited by means of selective biochemicals beyond a certain limit, this may possibly trigger apoptosis (programmed cell death) or necrosis (sudden cell death) in the targeted cells.  Generally it is not psooible to obtain the desired level of ATP Depletion by targeting only the mitochondrial oxidative phosphorylation or glycolysis alone but a combined approach should be considered.
 
For example the study  "Wages of fear": transient threefold decrease in intracellular ATP level imposes apoptosis shows that in HeLa cancer cells, complete inhibition of oxidative phosphorylation by oligomycin, myxothiazol or FCCP combined with partial inhibition of glycolysis by 2-Deoxy-D-Glucose (DOG) resulted in a steady threefold decrease in the intracellular ATP levels. The decrease in the ATP levels caused by the combination of oxidative phosphorylation and glycolysis inhibitors resulted in significant cell death by the programmed cell death apoptosis (blue columns) and necrotic cell death (red columns). When used alone the inhibitors did not cause severe ATP depletion or cell death as evident in the below figures.
 
 
 
 
 
Effect of ATP Depletion with Methylglyoxal in Cancer  
Methylglyoxal is a by-product of glycolysis and Prof. Albert Szent-Gyorgyi who received a nobel prize for the discovery of Vitamin C proposed in Keto-Aldehydes and Cell Division that Methylglyoxal along with glyoxalase enzyme has a key functin in regulating cell division. He also proposed that an adduct of Methylglyoxal with Vitamin C can be used as an effective anticancer agent.
 
Perhaps the major role of methylglyoxal is to regulate the production rate of ATP synthesis by acting as a brake. When too much ATP is used it is converted to ADP + P (Phosphate) by releasing its energy and increasing the level of P in the cell. In the cells methylglyoxal is primarily synthesized by the enzyme Methylglyoxal Synthase. As reviewed in the Cooper’s article Metabolism of methylglyoxal in microorganisms, when –P- levels become high in the cell this enzyme is inhibited and methylglyoxal is not synthesized. When methylglyoxal level is decreased the cell begins to start more ATP from ADP and P by reducing level of P. When P levels are reduced because of too much ATP production this time the enzyme Methylglyoxal Synthase begins to synthesize methylglyoxal again and it acts like a brake to reduce the ATP production.
 
Prof. Manju Ray who did several clinical studies with Methylglyoxal showed that Methylglyoxal significantly and selectively depletes ATP in cancer cells and along with Vitamin C and Creatine can be safely and effectively used to treat various forms of cancers. The outcomes of the phase II study on  cancer patients published in Treatment of a number of cancer patients suffering from different types of malignancies by methylglyoxal-based formulation: A promising result. showed that around 40% of the patients had complete remisson and another 40% had partial regression and/or stable disease while remaining patients had progressive disease.
 
The study In vivo assessment of toxicity and pharmacokinetics of methylglyoxal. Augmentation of the curative effect of methylglyoxal on cancer-bearing mice by ascorbic acid and creatine. evaluated both the toxicity and the efficacy of methylglyoxal in different animal models. Relatively large doses of methylglyoxal did not cause toxicity in dogs, rats, mice and rats. While 1000 mg/kg methylglyoxal did not cause toxic effects in mouse, only 30 mg/kg methylglyoxal combined with ascorbic acid and creatine in ehrlich ascites carcinoma bearing mouse completely eliminated tumors and cured 13 of 15 treated animals as shown in the table.

In the below images while huge tumor burden is apparent in the untreated mouse, methylglyoxal (MG) + ascorbic acid (AA) + creatine (CR) treated mouse looked as healthy as the normal mouse.

 
Normal Mouse 
Untreated Mouse 
Treated with MG only
Treated with MG + AA 
Treated with MG + AA + CR 
 
Effect of ATP Depletion with 3-Bromopyruvate in Cancer
3-Bromopyruvate is an analog of pyruvate that significantly inhibits both glycolysis and mitochondrial oxidative phosphorylation by causing a severe ATP depletion.
 
In the study Advanced cancers: eradication in all cases using 3-bromopyruvate therapy researchers showed that 3-bromopyruvate causes more than 90% ATP Depletion in cancer cells but not sigificantly affecting normal hepatocytes.
 
Also 3-bromopyruvate while selectively kills the AS-30D HCC cancer cells without affecting normal hepatocytes in much higher concentration as shown in the tables.  
 
In the same study through ATP Depletion 3-Bromopyruvate also was able to completely eliminate massive tumors in all the 19 treated animals without causing side effects.
 
In the next pictures you can see that how massive tumor were comletely eliminated in tumor bearing animals tht were being treated with 4 weeks with 3-Bromopyruvate.
 
 
Effect of ATP Depletion by Methyl Jasmonate and 2-Deoxy-D-Glucose in Cancer 
Methyl jasmonate(MJ), an inhibitor of mitochondrial oxidative in combination with the glycolytic inhibitor 2-Deoxy-D-Glucose (2DG) synergistically depletes the ATP levels significantly  more than obtained by each agent alone as shown in the study Cooperative cytotoxicity of methyl jasmonate with anti-cancer drugs and 2-deoxy-D-glucose.
 
This synergistic effect between two different types of ATP inhibitors is apparent in their combined toxicity against different tumor cell lines D122, MCF7 and CT26 as shown in the picture. 
 
 
 
 
 
 
 
 
 
 
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