Biology Reference
In-Depth Information
Fujii et al. (2007) designed a small-molecule inhibitor called FJ9. This disrupts
the interaction between the Fzd7 and the PDZ domain of DVL, so diminishing
canonical Wnt signalling. They also demonstrated that FJ9 suppressed tumour cell
growth
in vitro
with induction of apoptosis. Also it markedly suppressed growth of
xenografted human cancer cells. Small peptides that appear to inhibit Fzd7 activ-
ity by disrupting the Fzd-DVL have also been described by Nambotin et al. (2011).
These induced apoptosis of hepatocellular carcinoma cells
in vitro
. Using a trans-
genic murine tumour with many features corresponding with human hepatocellular
carcinoma, Nambotin et al. (2011) have been able to show intratumoral injection of
these peptides retarded tumour growth.
The importance of this approach of targeting aberrant Wnt signalling is under-
scored by its latent value in the management of TNBC. Transcriptional suppres-
sion of LRP6 or FZD7 in TNBC cells inhibits tumour growth
in vivo
. The TNBC
are most refractory to treatment by their very nature of being ER−/PR−/HER2−
and therefore show no response to tamoxifen, aromatase inhibitors or to Herceptin.
Around a tenth of breast cancers turning out to be triple negative, TNBCs are highly
aggressive and associated with enhanced recurrence and metastasis and poor prog-
nosis. Thus the problem of managing these patients assumes a serious dimension.
Several therapeutic avenues have been investigated, such as targeted DNA homol-
ogous recombination, inhibition of EGFR and VEGFR signalling, inhibitors of
mTOR, src kinase signalling and cell cycle checkpoint inhibitors, among others
(Sherbet, 2011a). Fzd7 and LRP6 are overexpressed in the triple negative breast
cancer cell lines MDA-MB-231 and BT-20 cells. Suppression of Fzd7 has led to
inhibition of cell proliferation and colony formation and invasion
in vitro
.
In vivo
formation of tumours from xenografting of cells with suppressed Fzd7 was also sig-
nificantly inhibited (Yang et al., 2011d).
In the context of TNBC, it would be worthwhile stating that Salinomycin has turned
out to be a useful inhibitor of Wnt signalling with associated consequent effects on
cell proliferation, apoptosis and migration. It is suggested to be a putative cancer stem
cell inhibitor. Salinomycin has been found to inhibit proliferation of breast cancer cells
and prostate cancer cells. In breast cancer cells, its inhibitory effect is over a 100-fold
greater than paclitaxel. The susceptibility of breast cancer cells to salinomycin corre-
lated with the proportion of CD44
high
/CD24
low
CSC cells. The antibiotic also inhib-
ited tumour growth in murine models with downregulation of genes associated with
the CSC phenotype (Gupta et al., 2009). In prostate cancer cells besides reducing the
numbers of cells, Salinomycin reduced the expression of myc, AR and ERG, induced
oxidative stress and inhibited NF-kB activity and cell migration (Ketola et al., 2012).
In osteosarcomas too, Salinomycin could be targeting stem cells by indication of its
effects on stem cell marker expression (Tang et al., 2011b). These authors have also
implicated interference with Wnt signalling. Interestingly, in Wnt-transfected HEK293
cells Salinomycin prevents phosphorylation and promotes the degradation of LRP6. In
CLL cells with constitutively activated Wnt, the antibiotic downregulated the expres-
sion of the transcription factor LEF1 and cyclin D1 (Lu et al., 2011a). With this back-
ground, it might be worthwhile pursuing Salinomycin in the treatment of TNBC. Quite
clearly this route has to traverse a long way, but most certainly it is worth the effort.
Search WWH ::
Custom Search