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modality to control tumour growth and progression. Liposome-mediated transfec-
tion of LKB1 (Lps-LKB1) into NSCLC has provided some encouraging results in
that intratumoral injection of Lps-LKB1 together with low-dose cisplatin inhib-
ited the growth of A549 tumour xenografts. Intravenous injection of Lps-LKB1
plus cisplatin also reduced pre-existing metastatic lung nodules. There was also
increase in survival of animals that received Lps-LKB1 plus cisplatin (Ou et al.,
2012).
It might be possible to take advantage of the ability of LKB1 to suppress pluri-
potency. Exploration of reactivation of LKB1 with miRNA such as Let-7 that can
suppress stem cell pluripotency is eminently worthy of consideration, especially
in the light of the expression of Lin28 a suppressor of Let-7, correlating strongly
with aggressive behaviour of tumours. Suppression of miRNA-199a-3p is said to
enhance LKB1 expression. Also activation of FXR (Farnesoid X receptor) reduces
levels of this miRNA in HepG2 cells (Lee et al., 2012). The non-steroidal synthetic
FXR ligand GW4064 (3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-
4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid) might provide a useful tool for
preliminary laboratory investigations. GW4064 markedly reduces cell viability as
tested on human HCC cell lines. It also inhibited cell viability synergistically with
acyclic retinoid (ACR), a synthetic retinoid targeting RXRα. The effect was by the
induction of apoptosis, and again there was synergy between the two agents. This
combination also induced G
0
/G
1
arrest (Ohno et al., 2012). Interestingly, FXR and its
agonists might exert additive effect by other means too. GW4064 can elevate plasma
glucocorticoid levels (Hoekstra et al., 2012), possibly a beneficial side effect in the
regulation of tumour growth. Also FXR is able to upregulate the expression of p62,
which induces autophagy and activate NF-κB towards cell survival and balance this
with induction of apoptosis by activation of caspase-8 (Williams et al., 2012). To
contrast with its effects on miRNA-199a-3p, GW4064 upregulates miRNA-29a in
quiescent hepatic stellate cells and notably miRNA-29a downregulates the expres-
sion of ECM proteins (Li et al., 2011a).
On the down side, some problems have been identified which might restrict the
use of this agonist. GW4064 has poor water solubility making it difficult to test bio-
availability. A vehicle containing Tween80, HPMC (hydroxypropyl methylcellulose),
Cremophor EL (a formulation vehicle used for drugs with poor solubility), polyeth-
ylene glycol 400/ethyl alcohol and Capmul MCM (a co-surfactant), was formulated
to overcome the problem of limited solubility (Chiang et al., 2011). Nevertheless,
assessing the efficacy of GW4064 in conjunction with the other agents that can
amplify efficacy might be rewarding. Also many novel and improved analogues have
been synthesised.
A possible novel approach would be to take advantage of the several interact-
ing and cross talking signalling pathways and press this advantage home by engag-
ing them into upregulation of LKB1 and reinstating its suppressor function. As
discussed earlier, oestradiol reduces LKB1 promoter activity (Brown et al., 2011).
Downregulation of ER/PR and deployment of anti-oestrogens might possibly be of
benefit in the restoration of LKB1 expression where transcription is repressed.
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