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was seen when administered with doxorubicin and mTOR inhibitor. The combination
treatment was more effective in inducing autophagy than when administered alone
(Shi et al., 2012). In ovarian cancer cells, Akt inhibition does compound the inhibi-
tory effects of metformin (Li et al., 2012b). Paclitaxel is a mitotic inhibitor capable
of promoting tubulin polymerisation to microtubules and stabilising them. It blocks
cell cycle progression in G2-M. It is an approved therapeutic agent in the manage-
ment of NSCLC, ovarian and breast cancer, and Kaposi sarcoma. Upon combination
with metformin, paclitaxel seems to add to the loss of cells by apoptosis induced by
metformin via AMPK activation and suppression of mTOR survival pathway with
cell cycle arrest at G2-M thus enhancing the overall growth inhibition (Rocha et al.,
2011). But Rocha et al. (2011) state that paclitaxel on its own could activate AMPK
and inhibit mTOR and its downstream targets. It may be that there is no indisput-
ably synergistic effect here, but one cannot exclude the possibility of AMPK inducing
acetylation and stabilisation of p53 which would induce apoptosis. AMPK also inac-
tivates the p53 deacetylase, SIRT1 (Lee et al., 2012), thus consolidating the acetyla-
tion, stability and activation of p53. One should also mention here that the mTOR
suppressor temsirolimus and the microtubule destabiliser vinblastine generate marked
anti-tumour effects with attendant suppression of anti-apoptosis and pro-survival pro-
teins survivin, Bcl-2, and Mcl-1 (Zhou et al., 2012b).
Metformin inhibited insulin-induced proliferation of ovarian theca-interstitial
cells with the upregulation of the cell cycle regulatory proteins, cyclin D3 and cdk4.
In this system, metformin is seen to function via activation of AMPK and inhibit-
ing ERK1/2 activation and the effects were blocked by the inhibition of AMPK by
compound C ((6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]
pyrimidine) (Will et al., 2012).
The apoptotic pathway has also been invoked in relation to LKB1/AMPK
repressor function. AMPK could be inducing apoptosis by the mitochondrial cas-
pase cascade and AIF. Also postulated is the participation of PI3K/Akt pathway
and MAPK/38-ERK signalling (Kim and Choi, 2012; Liu et al., 2012a). As shown
in
Figure 28.2
, AMPK might also be able to induce apoptosis by inhibiting mTOR
signalling and also NF-κB. Independently, AMPK can induce cell cycle arrest via
upregulation of cyclins and cdks. Inhibition of NF-κB survival pathway has also not
been excluded. Metformin suppresses its activation, and inhibition of both AMPK
and PTEN is able to restore NF-κB. Thus metformin might be a highly effective
growth suppressor using the vast versatility of AMPK functions drawing together
many signalling systems to suppress cell survival and induce apoptosis.
It is of much interest to note that metformin inhibits cell proliferation irrespective
of steroid or growths factor receptor status. It is inhibitory of ERα+, HER2+ as well
as TNBC cells (Liu et al., 2009, 2012a). Liu et al. (2009) have described TNBC-
specific inhibition of cell proliferation partly by cell cycle arrest and induction of
apoptosis. In parallel they could see the induction of phosphorylated AMPK and
reduced levels and activation of EGFR and also suppression of MAPK, src kinases,
cyclins D1 and E and finally enhancement of PARP cleavage indicating induction of
apoptosis. But then Alimova et al. (2009) have come up with all-inclusive signalling
process. Metformin was effective against ER+ and ER−, HER2 expressing breast
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