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inhibit tumour growth in vitro and in vivo . Of these Kovacevic et al. (2011a) found
di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride to be
a highly effective tumour inhibitor as studied in xenografts of pancreatic cancer cells
into BALBc nu/nu mice together with upregulation of NDRG1. Furthermore, this
compound appeared to be tumour-specific without inflicting significant changes in
normal tissues. Although the putative metastasis inhibitor was upregulated, there are
no indications whether the xenograft control tumours had metastasised and whether
the treatment regime besides completely inhibiting tumour growth also rendered
the host animals totally devoid of metastases. Another iron chelator that appears to
upregulate both NDRG1 and BTG2 (B-cell translocation gene 2) is l-Mimosine
which arrests cells at G1-S transition point, quite obviously the outcome of induction
by l-Mimosine and HIF-1α of both genes (Chung et al., 2012).
Luteolin Upregulates NDRG1
The flavonoid luteolin (3′,4′,5,7-tetrahydroxyflavone) is reputedly an inhibitor of
tumour growth and metastasis. It seems to be capable of inhibiting EMT (Lin et al.,
2011b). Hypoxia-induced EMT is inhibited by luteolin. It reversed EMT-associated
suppression of E-cadherin and increase of N-cadherin and vimentin. Luteolin also
inhibited the expression of integrin β1 and FAK, features closely related to EMT
(Ruan et al., 2012). The flavone possibly also functions by inhibiting PI3K/Akt and
NF-κB signalling to suppress cell proliferation and growth and invasion. Whether
NDRG1 is involved in the modulation of signalling by this cell survival pathway
is still unclear. The suppressor gene PTEN inhibits the PI3/Akt pathway and pro-
motes apoptosis. Unoki and Nakamura (2001) found that introduction of extra-
neous PTEN, presumably by gene transfer although not so stated, transactivated
several growth inhibitory genes that included NDRG1. Ostensibly NDRG1, which
was said to have been strongly induced, was investigated further. However no data
are provided, except that the increase in NDRG1 had had no effect on cell prolifera-
tion. The uncertainty of PTEN involvement heightens when read together with the
reported findings that NDRG1 upregulation correlated with the downregulation of
PTEN (Chen et  al., 2008a). Nonetheless a clearer picture emerges from Klawitter
et  al. (2010) showing that Lovastatin upregulated PTEN thus effectively inhibiting
Akt resulting in enhanced expression of NDRG1. Also earlier Bandyopadhyay et al.
(2004) had demonstrated the upregulation of NDRG1 by PTEN.
Treatment of LNCap prostate cancer cells with luteolin inhibits cell prolifera-
tion by cell cycle arrest at G1-S. This is accompanied by the enhanced expression of
many genes including NDRG1 (Tsui et al., 2012). The others upregulated are BTG2,
an NGF-inducible gene coding for a protein with anti-proliferative properties, and
Maspin, a serum proteinase inhibitor and a putative tumour suppressor. Maspin was
reported to inhibit motility of breast cancer and prostate cancer cells in vitro and in
fact it is epigenetically silenced in a number of human tumours (see pp. 129-132).
Both BTG2 and Maspin were shown some time ago to be regulated by p53 (Rouault
et al., 1996; Hendrix, 2000; Zou et al., 2000). Thus many of these agents that upreg-
ulate NDRG1 seem to function by p53-mediation, as discussed below.
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