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In-Depth Information
Metformin
NF- B
AMPK
Cyclins, cdks
Cell cycle arrest
mTOR
MAPK/p38
PTEN
ERK
PI3K/Akt
Apoptosis Cell proliferation
Apoptosis
Figure 28.2
Postulated signalling systems operating the metformin/AMPK-mediated
induction of apoptosis and inhibition of cell proliferation.
cancer and normal cells. Cell proliferation was due to G1-S transition, but without
induction of apoptosis. They also encountered MAPK, Akt and mTOR suppression
in cells irrespective of their steroid receptor and HER2 level of expression.
Significant from the point of view is the apparent inhibitory effects of metformin
on cancer metastasis. Rattan et al. (2011) injected A2780 ovarian cancer cells intra-
peritoneally into nude mice and studied tumour growth and dissemination. They
found that activation of AMPK and inhibition of mTOR signalling by metformin
suppressed angiogenesis as indicated by CD31 expression. Reduced microves-
sel density occurred with reduction in VEGF expression. Furthermore although
tumours occurred on the surface of liver, spleen and kidney, they were not invaded
by the tumour. Animals not treated with metformin showed deposition of tumour
in the lungs and this was reduced in the treated animals. Unfortunately details of
how immunohistochemistry results were assessed and graded have not been pro-
vided. Nonetheless, this is a highly creditable effort and if confirmed would be
invaluable. Quite obviously the authors are trying to portray a situation analogous
to human ovarian cancer where tumour spread occurs by peritoneal adhesion of cells
released from the primary lesion. So notwithstanding the demonstration that without
metformin treatment the tumours showed metastatic spread to the lungs, it is essen-
tial that cell surface determinants such as CA125 (MUC16), mesothelin and others
which promote peritoneal implantation should have been assessed. Some adhesion
molecules such as intercellular adhesion molecule (ICAM) might be influenced by
metformin. Germeyer et al. (2011) have noticed that metformin increased and insu-
lin decreased, but not beyond reasonable doubt, the expression of ICAM gene. But
earlier Bilgir et al. (2009) reported a marked reduction in soluble ICAM in patients
with polycystic ovary syndrome. In TNBC cells, metformin reduced CD24 expres-
sion (Vazquez-Martin et al., 2011).
Does Metformin Selectively Destroy CSCs?
LKB1/AMPK signalling has also been implicated in the suppression of CSCs.
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