Download PET Scans

PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
AEROBIC GLYCOLYSIS
AND CANCER:
AKT TARGETED
CANCER TREATMENT
Bahar Ameri
Yalda Zarghami
Tingxi (Cassie) Zhao
Samantha Wong
November 23, 2016
Upregulation of Glycolysis
Normal Differentiated Cells
Proliferative Cells
Mitochondrial Oxidative
Phosphorylation
Aerobic Glycolysis (Warburg Effect)
The Warburg Effect
PET Scans
 AKA Positron Emission Tomography
 An imaging test used to detect cancer
http://womensbrainhealth.org/wp-content/uploads/2012/04/petscan.jp
http://www.cerebromente.org.br/n01/pet/functpet.gif
 A radioactive dye such as fluorine-18
fluorodeoxyglucose (FDG) is taken into the
body.
 Fluorine-18 radioactive decay is picked up
by the PET machine
PET Scans and Glycolysis
FDG
hexokinase
FDG-6phosphate
×
Glycolysis
Accumulation
FDG is a glucose analogue, so cells uptake
it readily and easily.
Like glucose, FDG is phosphorylated by
hexokinase into FDG-6-phosphate in the first
step of glycolysis.
HOWEVER, unlike glucose-6-phosphate, FDG6-phosphate cannot continue through
glycolysis and just builds up in the cell.
Due to high glucose demand of cancerous
cells, a large amount of FDG-6-phosphate
accumulates in cancer cells, and these cell
masses are picked up by the PET machine.
glucose
hexokinase
glucose-6phosphate
Glycolysis
Serine/threonine kinase Akt:
■ In category of oncogenes
■ Activated downstream of phosophoinositide 3-kinase (PI-3K)
■ Sufficient to account for the switch to aerobic glycolysis in cancer cells
■ Promotes translocation of GLUT4 to plasma membrane, induces
GLUT1 gene transcription
■ Allows the cell to recycle NADH to NAD+
Benefits to a cancer cell with high
glycolytic rate:
1) Continually providing the mitochondrial electron transport chain with
substrates
2) Constant supply of substrates for biosynthetic processes
3) Oxidative arm of pentose phosphate cycle provides substrate for
production of NADPH
Classes of Treatments: Akt inhibitors
■ ATP-competitive inhibitor

Isoquinoline-5-sulfonamides
■ Allosteric inhibitors
 Perifosine
■ Irreversible inhibitor
 Lactoquinomycin
Alkylphospholipid
■ Subgroup of allosteric inhibitor
■ Interferes with phospholipids metabolism and survival signaling
■ Induce apoptosis
■ Inhibit neovascularization
■ Prevent invasion
Perifosine
■ APL
■ Inhibition of AKT
■ Induction of apoptosis via clustering of death receptors in lipid rafts
■ Passed phase I/II trials
■ Halted Phase III in 2012
Thank you for listening!
Summary
Intro
1.
Highly proliferative cells such as tumours rely on a process known as aerobic glycolysis or the Warburg effect for ATP
synthesis.
2.
Aerobic glycolysis is the upregulation of glycolysis for energy production despite the presence of sufficient oxygen for
mitochondrial oxidative phosphorylation.
3.
Aerobic glycolysis produces lactic acid as a metabolic side product and is an inefficient means for ATP production.
PET Scan
1.
PET (positron emission tomography) is an imaging test used to inspect body function and metabolism of organs and
tissues
2.
PET scanning uses a radioactive dye called fluorine-18 fluorodeoxyglucose (FDG), a glucose analogue.
3.
Due to high glucose demand in cancer cells, FDG is taken into cancerous cells in high amounts, which is then
phosphorylated into FDG-6-phosphate by hexokinase in the first step of glycolysis.
4.
However, FDG-6-phosphate is unable to continue through glycolysis so it accumulates in the cell. FDG-6-phosphate
can be picked up by the PET machine and high levels of accumulation could indicate cancerous tumour growth.
Akt
1.
Akt is in the category of oncogenes and is responsible for the switch to aerobic glycolysis in cancer cells.
Treatment
1.
Three classes of AKT inhibitors  ATP-competitive inhibitor, allosteric inhibitor, and irreversible inhibitor
2.
Perifosine is an allosteric inhibitor that would inhibit AKT or induce cell apoptosis.
References
Elstrom, R. L. (2004). Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Research, 64(11), 3892-3899.
doi:10.1158/0008-5472.can-03-2904
Fensterle, J., Aicher, B., Seipelt, I., Teifel, M., & Engel, J. (2014). Current view on the mechanism of action of perifosine in cancer.
Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 14(4), 629-635.
Krans, B. (2015, November). PET Scan. Retrieved from http://www.healthline.com/health/pet-scan
Lunt, S. Y., & Vander Heiden, M. G. (2011). Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annual
review of cell and developmental biology, 27, 441-464.
Nicholson, K. M., & Anderson, N. G. (2002). The protein kinase B/Akt signalling pathway in human malignancy. Cellular
Signalling, 14(5), 381-395. doi:10.1016/s0898-6568(01)00271-6
Nitulescu, G. M., Margina, D., Juzenas, P., Peng, Q., Olaru, O. T., Saloustros, E., … Tsatsakis, A. M. (2016). Akt inhibitors in cancer
treatment: The long journey from drug discovery to clinical use (Review). International Journal of Oncology, 48(3), 869–885.
http://doi.org/10.3892/ijo.2015.3306
Pal, S. K., Reckamp, K., Yu, H., & Figlin, R. A. (2010). Akt inhibitors in clinical development for the treatment of cancer. Expert
opinion on investigational drugs, 19(11), 1355-1366. Chicago
Positron emission tomography (PET) scan. (2016). Retrieved from http://www.cancer.ca/en/cancer-information/diagnosis-andtreatment/tests-and-procedures/positron-emission-tomography-pet-scan/?region=sk
Richardson, P. G., Eng, C., Kolesar, J., Hideshima, T., & Anderson, K. C. (2012). Perifosine, an oral, anti-cancer agent and inhibitor
of the Akt pathway: mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity. Expert opinion on drug
metabolism & toxicology, 8(5), 623-633.
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: the metabolic requirements
of cell proliferation. science, 324(5930), 1029-1033.
Zhu, A., Lee, D., Shim, H. (2011) Metablic PET Imaging in Cancer Detection and Therapy Response. Seminars in Oncology, 38(1),
55-69. Doi:10.1053/j.seminoncol.2010.11.012