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43518
Cancer and metabolism, pt.2
Descripción
Cancer Biology Mapa Mental sobre Cancer and metabolism, pt.2, creado por maisie_oj el 11/04/2013.
Sin etiquetas
cancer biology
cancer biology
Mapa Mental por
maisie_oj
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maisie_oj
hace más de 11 años
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Resumen del Recurso
Cancer and metabolism, pt.2
Role of metformin (antidiabetic drug) in cancer
Increases glucose uptake in adipocytes
Increase in lipid oxidation in muscle cells
Decrease in liver glucose production
Decreased insulinaemia (insulin signals via the insulin receptor -> acitvates both PI3K and Ras pathways)
Activation of Akt and MAPK -> activation of mTOR -> cell gorwth and protein synthesis (with inhibited apoptosis and autophagy)
Direct effects of metformin
Inhibits mTOR by...
Inhibition of complex 1 (inhibtion of oxidative phosphorylation) -> activation of AMPK (AMP-dependent kinase)
AMPK activates TSC1/2 -> inhibits mTOR
Inhibits RagGTPase (an activator of mTOR)
Activates p53 -> activates REDD1 -> inhibtis mTOR
alpha-ketoglutarate derivatives
Competes with succinate and fumarate for prolyl hydroxylase
In cancer... succinate and fumarate inhibit prolyl hydroxylase
No hydroxylation of HIF1-alpha and therefore no degradation (via VHL ubiquitination)
Using alpha-ketoglutarate derivatives (alpha-ketoglutarate is the normal substrate) overcomes and reverses this prolyl hydroxlation inhibition
Due to loss of SDH and FH
mTOR (ser/thr kinase) antagonists
Licensed for reneal cell cancer
e.g. evrolimus, temsirolimus
Activated mTOR (by GFs, amino acids, energy status, oxygen)
Protein synthesis
Apoptosis inhibition (cell survival)
Metabolism
By RTKs -> activation of Ras or PI3K pathway -> activation of mTOR
mTOR is a member of the PI3K family - therefore an effective treatment may include the dual blockade of both PI3K and mTOR
Amino acid metabolism and blood cancers
Asparagine as a target
Guinea-pig serum caused regression of lymphoma in a mouse model (Kidd, 1953) - active substance was L-asparaginase
L-asparaginase (produced in E. coli) now given in childhood ALL
All cells need asparagine for survival
Lymphoma cells (e.g. ALL) have repressed asparagine sythetase and therefore cannot synthesise asparagine - rely on asparagine from an outside source
Arginine as a target
Arginine is an essential amino acid - without it cells will die
If diet is deficient normal cells can synthesise argininosuccinate (made into arginine) by the enzyme argininosuccinate synthase (ASS1)
Using cellular aspartate+ citrulline
Several cancers (melanoma, hepatocellular carcinoma (HCC), mesothelioma and renal) lack ASS
Require an extracellular source
PEGylated (covalently added polyethylene glycol) arginine deaminase (ADI-PEG)
Converts arginine to citrulline and NH3
Promising signs in phase I/II trials in HCC and metastatic malignant melanoma (MMM)
Without arginine cells undergo apoptosis
Methylation of the ASS promoter [EPIGENETIC]
Low ASS is a sign for chemoresistance (particularly to platinum based drugs - cisplatin) and poor prognosis
Seen in MMM, HCC, osteosarcoma, mesothelioma, renal, pancreatic and prostate cancers
De-methylation as a treatment?
Indicates a poor prognosis
Malignant pleural mesothelioma (MPM)
Invariably fatal
80% of cases linked to earlier asbestos exposure
Long delay between exposure and disease
After diagnosis, survival is between 9-12 months
~2000 deaths each year
NICE guideline treatment - Platinum (cisplatin) and anti-folate (methotrexate)-based therapy (gives an extra 3 montsh at best)
Both inhibit enzymes involved in nucleotide synthesis for DNA and RNA
Other treatment - pemexetred (alimta)
Inhibits all enzymes involved in nucleotide synthesis: thymidylate synthase, dihydroxyfolate reductase (DHFR) and GARFT
Gives 12 months survival (in combination with standard therapy)
ASS expression in MPM
Many MPM cell lines have a low expression of ASS1
Associated with a poorer prognosis - 5 months (over 12 months in ASS+ve MPM)
Use of ADI-PEG 20 (arginine deaminase) reduces tumour size in MPM
ADAM trial
Szlosarek, 2013
Describe that the affects of ADI-PEG are neutralised by antibodies against it
Need to produce a less-antigenic version of ADI (human derived?)
Also describe the methylation of the ASS1 promotor in many MPM cell lines
Leading to supressed ASS1 transcription
Summary
Metabolism is dysregulated and is a key hallmark of cancer involved in invasion, metastasis, angiogenesis, survival etc.
Targeting cancer metabolism is an exciting area of current research and may provide novel therapeutic approaches
PREVENTION (E.G. CALORIFIC RESTRICITON) IS BETTER THAN THE CURE!
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