Download ATP Production from Fuel Oxidation

Sugar and Cancer
Glycolysis; Mitochondria and the Pentose Phosphate Pathway
“The one statistic that EXPOSES what an abysmal failure the war on
cancer has been is this: the death rates from cancer today, are the
SAME as they were in 1950.”
Robbwolf.com/2013/09/19 “The Origin of Cancer”
Dr. Kieron Rooney
[email protected]
@kieron_rooney
QuickTime™ and a
decompressor
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What have we missed?
› For the past 50 or so years, conventional wisdom in cancer research has
followed the “somatic mutation theory of cancer” / Cancer is a disease of
“Genetics”
- Caused by mutations that render certain biological systems dysfunctional (apoptosis)
- Most likely triggered by a genetic mutation or exposure to an environmental toxin (such
as smoking)
- This theory wasn’t always the case however
› 90 years ago German Biochemist - Otto Warburg (among others) viewed cancer
as a metabolic disease.
- The environmental toxin that caused cancer was sugar.
- This theory is experiencing a renaissance, a shift in focus from random DNA mutations
that cause cells to proliferate uncontrollably to specific metabolic disturbances that
provide the energy and metabolites for proliferation
- Thomas Seyfried, Dominic D’Agostino, Peter Pedersen, Mina Bissell, Lewis Cantley
Cell Energetics - All About “ATP”
Nutrient
Transporters
(Sugars or
Fats)
Cell Membrane (Fat
and Phosphate and
some proteins)
Cell Signal Receptors
(Growth Hormone, Insulin)
Glucose
Glucose
Glycolysis
ATP (108)
NAD
NADH (2)
Lactate
Fat
Proteins /
Amino
Acids
Fat
ATP (2)
Pyruvate (2)
Acetyl CoA
TCA
KREBS
Mitochondria
ATP (30)
Oxygen
NAD
NADH
(lots)
E
T
C
Warburg’s Cancer Cell Energetics - All About “ATP” (from
glycolysis only)
Glucose
Glucose
Glycolysis
400x
(Mina
Bissell)
NAD
NADH (2)
Lactate
Fat
Proteins /
Amino
Acids
Warburg Hypothesis: The
prime cause of cancer is the
replacement of the
respiration of oxygen in
normal body cells by the
fermentation of sugar
Fat
ATP (2)
Pyruvate (2)
?
Although Glycolysis is a
relatively inefficient fuel
supply in regard to ATP
production - It can
happen really really
fast (up to 200x the
rate of normal cells)
Mitochondrial Respiration is observed to be normal in
certain cancers and glucose restriction doesn’t always
stop cancer growth
› Vander Heiden MG et al. “Understanding the Warburg Effect: The Metabolic
Requirements of Cell Proliferation”. Science 324, 1029 (2009).
› Kim HH etal. “The Mitochondrial Warburg Effect: A Cancer Enigma”
Interdiscinplinary Bio Central doi: 10.4051/ibc.2009.2.0007 (2009).
› Roderiguez-Enriquez S et al. “The Warburg Hypothesis and the ATP Supply in
Cancer Cells is Oxidative Phosphorylation Impaired in Malignant Neoplasias?”
Curr Pharm Biotechnol (2012).
› Ma L et al. “Control of Nutrient Stress-Induced Metabolic Reprogramming by
PKC in Tumorigenesis. Cell 152, 599 (2013).
› So is the Warburg Hypothesis Wrong?
A Hypothesis is Never Wrong - Just in Need of
Refinement
› While the Warburg Hypothesis may need refining, The Warburg Effect is proving
to be highly reproducible across cancer cell types That is:
- A CONSISTENT FEATURE OF CANCER CELLS IS AEROBIC GLYCOLYSIS
› Of particular interest then is the how / why this occurs in the presence of
relatively normal functioning mitochondria that would be a more efficient energy
source?
- CELL METABOLISM IS NOT JUST ABOUT ENERGY
Cell Energetics - All About “Making New
cells”
Pentose Phosphate
Pathway
Glucose
Glucose
Glycolysis
Fructose
Lactate
(100s)
Pyruvate
(100s)
NADPH
DNA
Acetyl CoA
ATP
(100s)
Oxygen
Acetyl CoA
Glutamine
Ribose-5Phosphate
FAT
NADPH
NAD
NADH
TCA
KREBS
Mitochondria
Cell Membrane (Fat
and Phosphate and
some proteins)
NAD
NADH
(lots)
E
T
C
Conclusions?
› Glucose does appear to be a vital fuel for cancer cell growth. It is used by proliferating
cells to provide:
- Energy as ATP via glycolysis at rates far in excess to that of normal cells and mitochondrial
respiration
- An essential component of DNA synthesis in Ribose - 5 - Phosphate via the Pentose Phosphate
Pathway
- An essential component of Fat Synthesis in both NADPH from the PPP as well as Acetyl CoA via
glycolysis
› Could sugar restriction be a treatment plan for cancer?
- Cell Cultures and small animal studies tend to give mixed results depending on the type of cancer
- Published Human studies are few with varied designs but the literature base is growing
- It is likely that diet and drug treatment together will provide the most immediate, positive effects
- Previously reported associations between sugar intake, metabolic disease and cancer are now
being supported by basic science mechanisms - Sugar restriction is an achievable low risk option
for consideration
Human Studies of carbohydrate restriction and cancer:
› Nebeling LC et al “Effects of a ketogenic diet on tumor metabolism and nutritional
stauts in pediatric oncology patients: Two Case Reports J. Am. Coll. Nutr. 14(2),
202-208 (1995).
› Zuccoli G et al “Metabolic management of glioblastoma multiforme using
standard therapy together with a restricted ketogenic diet: Case Report. Nutr &
Metab 7:33 (2010).
› Schmidt M et al “Effects of a ketogenic diet on the quality of life in 16 patients
with advanced cancer: A pilot Trial. Nutr & Metab 8:54 (2011).
› Champ CE et al “Targeting metabolism with a ketogenic diet during the treatment
of glioblastoma multiforme” J Neurooncol doi: 10.1007/s11060-014-1362-0
(2014).
› Reviewed in:
› Klement RJ and Kammerer U “Is there a role for carbohydrate restriction in the
treatment and prevention of cancer?” Nutr & Metab 8: 75 (2011).