Biology Reference
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as well as c-Abl and NF-κB. The checkpoint kinases in turn target cdc25/cdc2
(Figure 14.2). ATM can directly activate p53 and via cdk1 and lead to G2/M arrest.
ATM can also use the p53/Chk2/cdc5 to produce the same effect. In other words, cell
cycle arrest can occur totally independently of AMPK.
AICAR and phenformin can both activate AMPK and lead to growth inhibition
when Raf/MEK/ERK signalling operates in the background (Petti et al., 2012).
Contraindicated is that AMPK activation might be inhibited by MAPK, but this has
given rise to the possibility of more effective AICAR mediation of growth inhibi-
tion when combined with MAPK inhibition. A useful combination especially in
the management of TNBCs might be of metformin to inhibit HER2 and activate
AMPKs. AICAR is said to be less efficient than metformin in inhibiting HER2
(Vazquez-Martin et al., 2012). HER2 has an inhibitory effect on AMPK and inhibi-
tors of HER2/EGFR have been found able to activate AMPK as Spector et al. (2007)
showed some time ago. So the inhibitory effects of AICAR and metformin on cell
proliferation might be further contributed to and compounded by HER2 inhibition
and the resultant restraint of its inhibition of AMPK. Resveratrol is another possibil-
ity. It has been found to activate AMPK irrespective of ER status (Lin et al., 2010).
AICAR has been shown to inhibit the mTOR pathway (Saha et al., 2011) and so
mTOR inhibitors might be another valid option for exploration.
Metformin Activates AMPK
Metformin is a biguanide which activates AMPKs and activation of the latter might
involve binding of metformin to the γ-subunit of AMPK (Zhang et al., 2012e).
Metformin is said to increase AMP/ATP ratio and this activates AMPK.
Metformin inhibits cell proliferation and exerts marked anti-inflammatory effects.
It has also been found to be an effective anti-cancer agent. The pathways of met-
formin function are being elucidated, but there are clear indications that it can arrest
cell cycle progression and induce apoptosis. A major effector is AMPK, but possi-
bly these effects might occur independently of AMPK. Brown et al. (2010) reported
that not only this activation but also found that LKB1 promoter activity is enhanced,
which in turn might potentiate AMPK activation. The inhibitory effect does seem to
be dependent upon LKB1.
AMPK activation has been achieved by gene transfer in cells not expressing LKB1
and there is some agreement that AMPK might function by the inhibition of mTOR
signalling and might also downregulate the ERK pathway (Klubo-Gwiezdzinska
et al., 2012; Xiao et al., 2012). Metformin activates AMPK and inhibits mTOR
signalling but it can also directly target mTOR quite independently of AMPK (see
Dowling et al., 2011). It activated AMPK and inhibited mTOR independently of
Akt in lymphoma tissues from a large number of patients with B- and T-cell lym-
phoma. Inhibition of AMPK resulted in upregulation of mTOR and its downstream
targets. Proliferation of established lymphoma cell lines was markedly inhibited by
metformin. The growth of Daudi and Jurkat tumour xenografts was also blocked by
intraperitoneal administration of metformin. A heightened growth inhibitory response
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