Ashikh Seethy

Junior Resident

Maulana Azad Medical College, New Delhi

Metabolic Alterations in Cancer

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.

Altered Metabolism in Cancer

• Carbohydrate metabolism:

Glucose transport

Glycolysis

• Kreb’s cycle

• Electron Transport Chain

• Amino acid metabolism:

Glutamine

• Lipid Metabolism

• Nucleotide Metabolism

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

Hypoxia Inducible Factor 1α

• Regulates ̴100 genes

• Angiogenesis- VEGF

• EZN-2968

• Aminoflavone

• Topetocan

• EZN 2208

Glycolysis:

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 -

• 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

Phosphofructokinase 1:

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

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

Lactate:

LDH inhibitors:GossypolFX-11

Pyruvate Dehydrogenase:

• Dichloro Acetate inhibits PDK1

• MELAS

• Phase 3 trials for Glioblastoma

Citric Acid Cycle:

Oncometabolite:A small chemical produced in the context of intermediate metabolism that is sufficient to promote oncogenesisfollowing its accumulation.

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

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

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

p53 and sCO2

• synthesis of Cyt. Oxidase 2

• Loss of p53 can impair Mitochondrial Respiration

Amino Acid Metabolism in Cancer:

• Asparagine:

L-Asparaginase in ALL

• Glutamine:

Phenyl acetate in Glioma

Lipids and Cancer:

Statins

ACLY

ACC

FAS

MembraneSignallingModification of proteinsMigration- PG, DAGAngiogenesis- PGE2

Altered Metabolism Helps in Cancer Imaging- PET and NMR Imaging

• PET• NMR

Warburg Effect: How and Why?

• Increased expression of glycolytic enzymes

• Damage to mtDNA and Oxidative Phosphorylation

Summary: