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metformin, in contrast with doxorubicin which was not able to target CSCs preferen-
tially in this way but did kill non-CSC cancer cells.
They also isolated CSC populations by flow cytometric cell sorting. CSCs were
highly susceptible to killing by metformin, whilst non-CSC tumour cells were virtu-
ally unaffected. But intriguingly tumour growth
in vivo
was suppressed only by a
combination of metformin and doxorubicin. Song et al. (2012a) have claimed that
they have noted a preferential deletion of high CD44/low CD24 expressing subpopu-
lation of MCF-7 breast cancer cells presumed to be CSCs, with reductions in size of
populations ranging from around 3% to 1%. They have also argued that metformin-
activated AMPK with concomitant reduction in levels of phosphorylated mTOR and
its downstream effectors S6K1 and 4EBP1. The suppression of the mTOR pathway
by metformin is well documented. But here mTOR suppression would occur as a
general effect in the population and so somewhat difficult to link it up with the per-
ceived reduction in the CSCs. Experimentally inactivating LKB1 might collaborate
with activated oncogenic factors to promote the survival of CD24+ cells suggestive
of CSC population expansion. The CD24+ cell population also showed increased
metastatic behaviour in comparison with CD24- cells (Liu et al., 2012e).
In general research circles CD44, CD133, CD24 and ESA are employed in the
identification of CSCs. Among these the status of CD24 is somewhat uncertain, but
it has been associated with pancreatic cancer and invasive breast cancer (Baumann
et al., 2005; Li et al., 2007b). As discussed above, CD24+ do represent a tumori-
genic fraction and indeed can and should be regarded as a marker of CSCs. Cells
expressing CD44+ phenotype are associated with initiation of many forms of can-
cer, for example the breast, colon, pancreas and the prostate. ESA is the favoured
phenotype of breast and pancreatic cancer CSCs. CD133 has been linked with glio-
blastoma, and colon and prostate cancers (Al-Hajj, 2003; Collins, 2005; Gudjonsson,
2002; O'Brien, 2007; Singh et al., 2004). It is needless to say that great care has
to be exercised in employing CSC markers. Recently ALDH (aldehyde dehydroge-
nase) has been touted as a CSC marker. The ALDH isoform ALDH1A3 has been
suggested to identify breast CSCs (Marcato et al., 2011). In the light of this, it is
interesting to note that metformin has been shown to inhibit the growth
in vitro
of
ovarian ALDH-expressing cells (Shank et al., 2012).
Application of Metformin in Cancer Management
Numerous clinical trials are in progress on the efficacy of metformin as a single
agent or in combination with standard chemotherapy as an anti-cancer agent by eval-
uating biological and molecular markers related to tumour growth. Markers of cell
proliferation and apoptosis, which are not indisputable and appropriate as markers of
metastasis, are frequently employed, but one needs trials to assess clinical endpoints.
Many tumour types are being studied.
Possible effects of CSCs are also being evaluated. Metformin has been cred-
ited with a preventive and protective role against cancer, but this view has not had
wide acceptance. At present there is no incontestable evidence that metformin
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