Targeting Cancer Metabolism
Summary:
References:
1. Targeting cancer metabolism – aiming at a tumour’s sweet-spot
"TABLE 1
Summary table of potential drugs/compounds targeting cancer metabolism. Examples listed are of published compounds or pipeline candidates that are designed to target cancer metabolism pathways and, where possible, details of molecular target, biological rationale/validation and status are given.
Drug/compound (Source/reference) Molecular or pathway target Biological validation Current status (if known)
Phloretin GLUT1/4 Blocks glucose uptake Early development
2-Deoxyglucose Hexokinase (glycolysis) Blocks glycolytic flux Reported in clinical trials
3-Bromopyruvate Hexokinase (+ other glycolytic targets?) Blocks glycolytic flux Preclinical development
Lonidamine Hexokinase Blocks glycolytic flux Clinical trials ongoing
3PO [+ derivatives] (Advanced Cancer Therapeutics) Phosphofructose kinase 2 [PFKFB3] Blocks positive regulation of PFK1 and glycolysis Preclinical development
Cap-232/TLN-232 (Thallion Pharmaceuticals) Pyruvate kinase-M2 Blocks pyruvate formation via PK route Trial suspended owing to licensing dispute (Agios Pharmaceuticals)
Pyruvate kinase-M2 Blocks pyruvate formation via PK route Preclinical (Agios Pharmaceuticals)
Pyruvate kinase-M2 activators Promotes glycolytic flux reducing synthesis of biosynthetic intermediates Preclinical
Dichloroacetate Pyruvate dehydrogenase kinase (+ metabolic targets?) Activates PDH and promotes oxidative phosphorylation Basic Phase I trial completed, Phase II studies proposed
FX11 (University of New Mexico/ The John Hopkins University) Lactate dehydrogenase Blocks metabolic flux pathways Early development
Oxamate Lactate dehydrogenase and aspartate aminotransferase Blocks metabolic flux pathways Early development
Amino oxyacetate Aspartate aminotransferase Blocks metabolic flux pathways Early development
AZD-3965 (AstraZeneca) MCT1 Blocks lactate secretion Phase I/II trials planned with CR:UK
5-Dehydroepiandrosterone [DHEA] Glucose-6-phosphate dehydrogenase + multiple non-metabolism targets Blocks oxidative pentose phosphate pathway (PPP) Early development
Oxythiamine Transketolase Blocks non-oxidative PPP Early development
(Tarvagenix) Transketolase-like 1 (TKTL1) Could block non-oxidative PPP in cancer Early development (no published data)
6-Diazo-5-oxo-L-norleucine Glutaminase (glutaminolysis) Blocks glutamine conversion to glutamate Toxicity issue Early development
968 (Cornell University) Glutaminase Blocks glutamine conversion to glutamate Early development
BPTES Glutaminase Blocks glutamine conversion to glutamate Early development
GSK837149A (GSK) Fatty acid synthase Blocks fatty acid synthesis Preclinical
Orlistat (Roche) Fatty acid synthase Blocks fatty acid synthesis Preclinical
C75 Fatty acid synthase Blocks fatty acid synthesis Early development
SB-204990 (GSK) ATP citrate ligase Blocks fatty acid synthesis Preclinical
(Agios Pharmaceuticals) Mutant IDH1/2 Blocks alternative catalytic function of mIDH Preclinical
CPI-163 (Cornerstone Pharmaceutical) Glycolytic target Blocks glycolytic flux Phase I/II trials ongoing
Metformin Energy sensing pathways (AMPK) and other targets Blocks lipid and protein synthesis and glycolytic regulation Used in diabetes, clinical trials in cancer ongoing
MPC-9528 (Myrexis) Nicotinamide phosphoribosyltransferase Blocks NAD production and reduces glycolysis Preclinical"
---------------------------------------------------------------
2. ATP targeting (link):
"All cells need energy to survive and they obtain it from the food we eat. However there are significant differences between the energy metabolism of malignant cells and normal cells. Cancer cells need to generate significantly more energy in a short period of time in order to rapidly proliferate as synthesizing new molecules requires a lot of energy. Several researchers propose that excessive ATP (universal energy currency of the cells) production may force a cell to a premature cell division which later on may lead to malignancy.
The fundamental differences between healthy cells and malignant cells on their energy production can be targeted and cancer cells can be selectively killed by starving them to death. I believe that the formation and promotion of cancer is taking place per the following route:
1- Mutations, free radical damage, carcinogens etc cause a damage in the energy metabolism regulation of a healthy cells where they produce excessive amounts of ATP that they cannot consume in normal metabolic activities.
2- This excessive ATP forces the cells to a premature cell division bypassing normal controls regulating cell division.
3- At the initial cancer formation stage the excessive ATP is mainly produced by the mitochondria as recent evidence showed that mitochondria can actively initiate cell division.
4- When the cancer cells increase in number they begin to make small spheres (tumors). The inner parts of the tumors cannot get enough oxygen and nutrients and the enzyme Hypoxia Inducible Factor HIF-I is overexpressed in such cancer cells
5- HIF-I causes a switch from mitochondrial oxidative phosphorylation to glycolysis (where ATP is generated in the cytoplasm without the use of oxygen in an inefficient way).
6- The inner cores or the hypoxic (low oxygen) parts of the tumors begin to depend more on glycolysis and become less active but the outer rings of the tumor spheroids continue to rely on the efficient mitochondrial ATP generation to obtain the much needed energy to rapidly proliferate.
In general cancer cells consume much higher amounts of glucose than normal cells, may have enhanced glycolysis even in the presence of oxygen and significantly altered mitochondrial characteristics. These altered features of cancer cells can be selectively targeted. Several agents that are used in clinical trials or in actual treatments to try to deplete the ATP selectively in cancer cells showed promising outcomes including the following molecules:
Acetogenins such as Paw Paw Extracts
Dichloroacetic acid –DCA-
Methyl Jasmonate
Methylglyoxal
2-Deoxyglucose
3-Bromopyruvate
Vitamin E Succinate
Generally these agents are selectively toxic to cancer cells while not affecting healthy cells at much higher concentrations. As tumors may contain both glycolysis and oxidative phophorylation dependent cells, either using multiple agents to block both energy generation routes or using the agents that affect both types of energy production may be needed. Most of these agents showed synergy when used in combination with conventional treatments such as chemotherapy and radiotherapy.
My personal view is that a successful cancer treatment program should contain agents or strategies that target the altered energy metabolism of malignant cells. I have been conducting research in this field for quite sometime and noticed that there is a significant amount of scientific literature pointing out to the efficacy of ATP depleting strategies. The next generation of cancer targeting agents will probably be focusing more on the energy metabolism of cancer cells. It is worthwhile to dig into this area for patients seeking alternative treatments who have exhausted most other options without significant benefits.
...
Additionally several other widely used supplements that target the energy metabolism of cancer cells as part of their toxicity against them are being discussed including but not limited to the following:
Curcumin
Luteolin
Maitake D-Fraction"
--------------------------------------------------
3. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells.
4. http://www.ketogenic-diet-resource.com/cancer-diet.html
http://www.dietarytherapies.com/ketogenic-diet-home.html
5. Targeting cancer cell metabolism
Beating Cancer With Food with Dr John Whitcomb Board Certified in Holistic and Integrative Medicine
Note: discusses diets (including ketogenic diet) and mentions iron chelation, artemisinin, decoppering therapy,
hyperthermia (with increased acidity of cancer cells ?!?), metformin
6. A Mitochondrial Etiology of Metabolic and Degenerative Diseases, Cancer and Aging
7. Thomas Seyfried: Cancer: A Metabolic Disease With Metabolic Solutions
Thomas N. Seyfried
Professor of biology, Ph.D., University of Illinois, Urbana-Champaign
E-mail: [email protected]
(mentions in video that can send list of MDs that can work with cancer patients using the ketogenic diet)
The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of
brain cancer
The role of metabolic therapy in treating glioblastoma multiforme
Metabolic therapy: a new paradigm for managing malignant brain cancer.
Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6J mice
Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer
Note: ketone ester
Ketone Strong: Emerging evidence for a therapeutic role of ketone bodies in neurological and neurodegenerative diseases
8. Dominic D'Agostino: Metabolic Therapies: Therapeutic Implications and Practical Application
Dominic D'Agostino
9. Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration
Anti-Cancer Agents to Treat Hypoxic Tumors
MCT1 inhibitors:
DIDS, CHC, luteolin
The Drug of Abuse γ-Hydroxybutyrate Is a Substrate for Sodium-Coupled Monocarboxylate Transporter (SMCT) 1
(SLC5A8): Characterization of SMCT-Mediated Uptake and Inhibition
"luteolin and CHC are specific MCT1 inhibitors"
Pharmacokinetic Interaction between the Flavonoid Luteolin and γ-Hydroxybutyrate in Rats: Potential Involvement
of Monocarboxylate Transporters
10. pH buffering to reduce metastasis
Buffer Therapy for Cancer
"meats and dairy foods are those with highest pH buffering score, while the carbonated sodas and citric juices have the lowest scores"
Bicarbonate increases tumor pH and inhibits spontaneous metastases.
11. Iron chelation
The Iron Chelator, Deferasirox, as a Novel Strategy for Cancer Treatment: Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action
The role of iron chelation in cancer therapy.
12. Decoppering therapy
Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry
Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study.
Supplements and medications that reduce Cu: Zinc, pychnogenol, vit. C, penicillamine, trientine
1. Targeting cancer metabolism – aiming at a tumour’s sweet-spot
"TABLE 1
Summary table of potential drugs/compounds targeting cancer metabolism. Examples listed are of published compounds or pipeline candidates that are designed to target cancer metabolism pathways and, where possible, details of molecular target, biological rationale/validation and status are given.
Drug/compound (Source/reference) Molecular or pathway target Biological validation Current status (if known)
Phloretin GLUT1/4 Blocks glucose uptake Early development
2-Deoxyglucose Hexokinase (glycolysis) Blocks glycolytic flux Reported in clinical trials
3-Bromopyruvate Hexokinase (+ other glycolytic targets?) Blocks glycolytic flux Preclinical development
Lonidamine Hexokinase Blocks glycolytic flux Clinical trials ongoing
3PO [+ derivatives] (Advanced Cancer Therapeutics) Phosphofructose kinase 2 [PFKFB3] Blocks positive regulation of PFK1 and glycolysis Preclinical development
Cap-232/TLN-232 (Thallion Pharmaceuticals) Pyruvate kinase-M2 Blocks pyruvate formation via PK route Trial suspended owing to licensing dispute (Agios Pharmaceuticals)
Pyruvate kinase-M2 Blocks pyruvate formation via PK route Preclinical (Agios Pharmaceuticals)
Pyruvate kinase-M2 activators Promotes glycolytic flux reducing synthesis of biosynthetic intermediates Preclinical
Dichloroacetate Pyruvate dehydrogenase kinase (+ metabolic targets?) Activates PDH and promotes oxidative phosphorylation Basic Phase I trial completed, Phase II studies proposed
FX11 (University of New Mexico/ The John Hopkins University) Lactate dehydrogenase Blocks metabolic flux pathways Early development
Oxamate Lactate dehydrogenase and aspartate aminotransferase Blocks metabolic flux pathways Early development
Amino oxyacetate Aspartate aminotransferase Blocks metabolic flux pathways Early development
AZD-3965 (AstraZeneca) MCT1 Blocks lactate secretion Phase I/II trials planned with CR:UK
5-Dehydroepiandrosterone [DHEA] Glucose-6-phosphate dehydrogenase + multiple non-metabolism targets Blocks oxidative pentose phosphate pathway (PPP) Early development
Oxythiamine Transketolase Blocks non-oxidative PPP Early development
(Tarvagenix) Transketolase-like 1 (TKTL1) Could block non-oxidative PPP in cancer Early development (no published data)
6-Diazo-5-oxo-L-norleucine Glutaminase (glutaminolysis) Blocks glutamine conversion to glutamate Toxicity issue Early development
968 (Cornell University) Glutaminase Blocks glutamine conversion to glutamate Early development
BPTES Glutaminase Blocks glutamine conversion to glutamate Early development
GSK837149A (GSK) Fatty acid synthase Blocks fatty acid synthesis Preclinical
Orlistat (Roche) Fatty acid synthase Blocks fatty acid synthesis Preclinical
C75 Fatty acid synthase Blocks fatty acid synthesis Early development
SB-204990 (GSK) ATP citrate ligase Blocks fatty acid synthesis Preclinical
(Agios Pharmaceuticals) Mutant IDH1/2 Blocks alternative catalytic function of mIDH Preclinical
CPI-163 (Cornerstone Pharmaceutical) Glycolytic target Blocks glycolytic flux Phase I/II trials ongoing
Metformin Energy sensing pathways (AMPK) and other targets Blocks lipid and protein synthesis and glycolytic regulation Used in diabetes, clinical trials in cancer ongoing
MPC-9528 (Myrexis) Nicotinamide phosphoribosyltransferase Blocks NAD production and reduces glycolysis Preclinical"
---------------------------------------------------------------
2. ATP targeting (link):
"All cells need energy to survive and they obtain it from the food we eat. However there are significant differences between the energy metabolism of malignant cells and normal cells. Cancer cells need to generate significantly more energy in a short period of time in order to rapidly proliferate as synthesizing new molecules requires a lot of energy. Several researchers propose that excessive ATP (universal energy currency of the cells) production may force a cell to a premature cell division which later on may lead to malignancy.
The fundamental differences between healthy cells and malignant cells on their energy production can be targeted and cancer cells can be selectively killed by starving them to death. I believe that the formation and promotion of cancer is taking place per the following route:
1- Mutations, free radical damage, carcinogens etc cause a damage in the energy metabolism regulation of a healthy cells where they produce excessive amounts of ATP that they cannot consume in normal metabolic activities.
2- This excessive ATP forces the cells to a premature cell division bypassing normal controls regulating cell division.
3- At the initial cancer formation stage the excessive ATP is mainly produced by the mitochondria as recent evidence showed that mitochondria can actively initiate cell division.
4- When the cancer cells increase in number they begin to make small spheres (tumors). The inner parts of the tumors cannot get enough oxygen and nutrients and the enzyme Hypoxia Inducible Factor HIF-I is overexpressed in such cancer cells
5- HIF-I causes a switch from mitochondrial oxidative phosphorylation to glycolysis (where ATP is generated in the cytoplasm without the use of oxygen in an inefficient way).
6- The inner cores or the hypoxic (low oxygen) parts of the tumors begin to depend more on glycolysis and become less active but the outer rings of the tumor spheroids continue to rely on the efficient mitochondrial ATP generation to obtain the much needed energy to rapidly proliferate.
In general cancer cells consume much higher amounts of glucose than normal cells, may have enhanced glycolysis even in the presence of oxygen and significantly altered mitochondrial characteristics. These altered features of cancer cells can be selectively targeted. Several agents that are used in clinical trials or in actual treatments to try to deplete the ATP selectively in cancer cells showed promising outcomes including the following molecules:
Acetogenins such as Paw Paw Extracts
Dichloroacetic acid –DCA-
Methyl Jasmonate
Methylglyoxal
2-Deoxyglucose
3-Bromopyruvate
Vitamin E Succinate
Generally these agents are selectively toxic to cancer cells while not affecting healthy cells at much higher concentrations. As tumors may contain both glycolysis and oxidative phophorylation dependent cells, either using multiple agents to block both energy generation routes or using the agents that affect both types of energy production may be needed. Most of these agents showed synergy when used in combination with conventional treatments such as chemotherapy and radiotherapy.
My personal view is that a successful cancer treatment program should contain agents or strategies that target the altered energy metabolism of malignant cells. I have been conducting research in this field for quite sometime and noticed that there is a significant amount of scientific literature pointing out to the efficacy of ATP depleting strategies. The next generation of cancer targeting agents will probably be focusing more on the energy metabolism of cancer cells. It is worthwhile to dig into this area for patients seeking alternative treatments who have exhausted most other options without significant benefits.
...
Additionally several other widely used supplements that target the energy metabolism of cancer cells as part of their toxicity against them are being discussed including but not limited to the following:
Curcumin
Luteolin
Maitake D-Fraction"
--------------------------------------------------
3. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells.
4. http://www.ketogenic-diet-resource.com/cancer-diet.html
http://www.dietarytherapies.com/ketogenic-diet-home.html
5. Targeting cancer cell metabolism
Beating Cancer With Food with Dr John Whitcomb Board Certified in Holistic and Integrative Medicine
Note: discusses diets (including ketogenic diet) and mentions iron chelation, artemisinin, decoppering therapy,
hyperthermia (with increased acidity of cancer cells ?!?), metformin
6. A Mitochondrial Etiology of Metabolic and Degenerative Diseases, Cancer and Aging
7. Thomas Seyfried: Cancer: A Metabolic Disease With Metabolic Solutions
Thomas N. Seyfried
Professor of biology, Ph.D., University of Illinois, Urbana-Champaign
E-mail: [email protected]
(mentions in video that can send list of MDs that can work with cancer patients using the ketogenic diet)
The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of
brain cancer
The role of metabolic therapy in treating glioblastoma multiforme
Metabolic therapy: a new paradigm for managing malignant brain cancer.
Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6J mice
Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer
Note: ketone ester
Ketone Strong: Emerging evidence for a therapeutic role of ketone bodies in neurological and neurodegenerative diseases
8. Dominic D'Agostino: Metabolic Therapies: Therapeutic Implications and Practical Application
Dominic D'Agostino
9. Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration
Anti-Cancer Agents to Treat Hypoxic Tumors
MCT1 inhibitors:
DIDS, CHC, luteolin
The Drug of Abuse γ-Hydroxybutyrate Is a Substrate for Sodium-Coupled Monocarboxylate Transporter (SMCT) 1
(SLC5A8): Characterization of SMCT-Mediated Uptake and Inhibition
"luteolin and CHC are specific MCT1 inhibitors"
Pharmacokinetic Interaction between the Flavonoid Luteolin and γ-Hydroxybutyrate in Rats: Potential Involvement
of Monocarboxylate Transporters
10. pH buffering to reduce metastasis
Buffer Therapy for Cancer
"meats and dairy foods are those with highest pH buffering score, while the carbonated sodas and citric juices have the lowest scores"
Bicarbonate increases tumor pH and inhibits spontaneous metastases.
11. Iron chelation
The Iron Chelator, Deferasirox, as a Novel Strategy for Cancer Treatment: Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action
The role of iron chelation in cancer therapy.
12. Decoppering therapy
Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry
Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study.
Supplements and medications that reduce Cu: Zinc, pychnogenol, vit. C, penicillamine, trientine