Metabolic Alterations in Cancer
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Transcript of Metabolic Alterations in Cancer
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Ashikh Seethy
Junior Resident
Maulana Azad Medical College, New Delhi
Metabolic Alterations in Cancer
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Introduction:• Pasteur effect: Normal cells consume less glucose and
produce less lactate in presence of O2.
• Otto Warburg: Under aerobic conditions, tumor tissues metabolise ~ 10 times more glucose to lactate than normal tissue.
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Altered Metabolism in Cancer
• Carbohydrate metabolism:
Glucose transport
Glycolysis
• Kreb’s cycle
• Electron Transport Chain
• Amino acid metabolism:
Glutamine
• Lipid Metabolism
• Nucleotide Metabolism
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Glucose Transport into Tumor Cells:
Glucose Transporter KM Value Location
GLUT 1 1 mM Brain, RBC, Kidney, Colon
GLUT 2 15-20 mM Liver, Small Intestine, β-cell
GLUT 3 1 mM Brain, Kidney
GLUT 4 5 mM Muscle, Adipose tissue
GLUT 5 - Small Intestine, Sperms
HIF1αPI3K-AKTRASATMC-MYC
p53
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Hypoxia Inducible Factor 1α
• Regulates ̴100 genes
• Angiogenesis- VEGF
• EZN-2968
• Aminoflavone
• Topetocan
• EZN 2208
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Glycolysis:
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Hexokinase:
HK II:
HKII: Not expressed in normal tissues
In hepatomas and islet cell tumors HK IV is silenced and HK II, is switched-on.
Hexokinase Inhibitors: Lonidamine
3-Bromopyruvate
Imatinib
Isoform Mol. Wt KM N-HyrophobicResidues
HK I 100 kDa 0.02 mM +
HK II 100 kDa 0.02 mM +
HK III 100 kDa 0.02 mM -
HK IV 050 kDa 5 mM -
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• The proven ability of lonidamine to inhibit energy metabolism in cancer cells and to enhance the activity of other anticancer agents has led to clinical trials (phase II–III) of this compound in combination with other anticancer agents for the treatment of breast cancer, glioblastoma multiforme, ovarian cancer, and lung cancer
• Animal studies showed that 3-BrPA has significant in vivo therapeutic activity against liver cancer when the compound was given by local infusion, and seems to inhibit metastasis when given intravenously
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Phosphofructokinase 1:
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TP53-Induced Glycolysis and Apoptosis Regulator: TIGAR
• Kinase activity
• ↑ F-2,6-BP
• Stimulates PFK1 and glycolysis
• Angiogenesis
• RAS and MYC, Hypoxia
• 1-(4-pyridinyl)-3-(2quinolinyl)-2-propen-1-one (PFK15)
6-PhosphoFructo-2-Kinase (PFKFB3)
• Phosphatase activity
• ↓ F-2,6-BP
• Inhibits PFK1 and glycolysis
• Anti-oxidant [PPP]
• Regulated by p53 in normal cells
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Pyruvate Kinase4 isoforms:Isoform Gene Location
L PKLR Liver, kidney, intestine
R PKLR RBC
M1 PKM Most adult tissues
M2 PKM Embryonic cells, stem cells, Cancer Cells
PKM2 activators:TEPP-46Serine
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Lactate:
LDH inhibitors:GossypolFX-11
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Pyruvate Dehydrogenase:
• Dichloro Acetate inhibits PDK1
• MELAS
• Phase 3 trials for Glioblastoma
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Citric Acid Cycle:
Oncometabolite:A small chemical produced in the context of intermediate metabolism that is sufficient to promote oncogenesisfollowing its accumulation.
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Isocitrate Dehydrogenase is an Onco-enzyme:
• IDH3 is the Kreb’s cycle enzyme.
• In 2008, IDH1 and IDH2 mutations were found in GBM and and AML.
• R132 in IDH1; R172 and R140 in IDH2
• IDH is used in diagnosis of GBM
• IDH inhibitors
AGI-5198 and AGI-6780
• 2-HG competes with αKG
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Succinate and Fumarate are Oncometabolites:
• Mutations in the FH [Fumarase] cause Hereditary Leiomyomatosis and Renal Cell Cancer- HLRCC
• Fumarate competes with α-KG
• Succination of Cysteine residues
• Mutations in SDH ↑ Succinate Competes with α-KG
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Electron Transport Chain:
MetforminHowever, it is of interest to ask why biguanides (like metformin) are not as toxic as well knownpoisons that inhibit oxidative phosphorylation, such as cyanide. One proposal is that biguanidesrequire active transport into mitochondria, and that as they reduce mitochondrial function, thistransport is inhibited, leading to a dynamic equilibrium, which limits the magnitude of theireffect
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p53 and sCO2
• synthesis of Cyt. Oxidase 2
• Loss of p53 can impair Mitochondrial Respiration
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Amino Acid Metabolism in Cancer:
• Asparagine:
L-Asparaginase in ALL
• Glutamine:
Phenyl acetate in Glioma
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Lipids and Cancer:
Statins
ACLY
ACC
FAS
MembraneSignallingModification of proteinsMigration- PG, DAGAngiogenesis- PGE2
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Altered Metabolism Helps in Cancer Imaging- PET and NMR Imaging
• PET• NMR
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Warburg Effect: How and Why?
• Increased expression of glycolytic enzymes
• Damage to mtDNA and Oxidative Phosphorylation
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Summary:
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