Nucleotide-Binding Oligomerization Domain 1 (NOD1), highly ex-
pressed in tumors in general, has been reported to be associated with
apoptosis, which could initiate NF-
κB-dependent and MAPK-dependent
gene transcription [
86
,
87
]. Based on previous study, NOD1, p-JNK, p-
P65, p-p38 and p-ERK are declined, while the level of I
κBα is elevated
in HCC cells when treated with evodiamine [
88
]. From these results,
evodiamine is able to reduce the expression of NOD1, resulting in the
suppression of NF-
κB and MAPK activation pathways. Furthermore,
evodiamine promotes apoptosis in HepG2 and SMMC-7721 cells via
inhibiting NOD1 signal pathway [
88
]. The protein expressions of p-AKT
and Bcl-2 in HepG2 cells are declined, and the protein levels of Bax,
cleaved-PARP and cleaved-caspase3 show a signi
ficant upregulation,
which suggests that evodiamine suppresses AKT and regulates apoptotic
proteins in HCC cells [
89
]. In addition, evodiamine can also achieve
anti-hepatocarcinoma by inhibiting the cell cycle. The percentage of
cells in the (G0/G1) is decreased, while little change is observed in DNA
replication phase (S), leading to the accumulation of cell population in
G2/M phase when HCC cells exposed to evodiamine [
89
]. WWOX (WW
Domain-Containing Oxidoreductase, OMIM 605131) as a multi-
functional protein, interacts with many proteins in di
fferent pathways.
Its overexpression is able to suppress tumor growth, promote apoptosis,
and inhibit cell cycle [
90
,
91
]. Evodiamine dose-dependently increases
the expression of WWOX in both HepG2 cells and Hepa1-6 cells, in-
dicating that evodiamine exerts the inhibition activity of liver cancer
cell growth via a WWOX-dependent pathway [
92
]. Moreover, the anti-
tumor e
ffect of evodiamine depends on its inhibition effect of angio-
genesis and metastasis [
93
]. Vascular endothelial growth factor (VEGF),
known as a key mediator of angiogenesis (
Fig. 4
), is regulated by few
interacting cellular pathways and it can be produced by overexpression
of
β-catenin, which plays an vital role in tumor immune [
94
,
95
].
Proved by some researchers, evodiamine decreases the levels of
β-ca-
tenin and VEGFa in H22 xenograft tumor tissue and attenuates VEGF-
induced
angiogenesis
in
SMMC-7721
xenograft
model
[
95
].
Evodiamine a
ffects the DNA-binding activity of β-catenin and VEGFa,
and also inhibits the protein expression of VEGFa through
β-catenin,
which shows that evodiamine reduces VEGFa expression through
β-
catenin in HCC cells [
93
]. It can be seen from these results that evo-
diamine exerts anti-tumor e
ffects against HCC by inhibiting β-catenin-
mediated angiogenesis. Furthermore, evodiamine suppresses cellular
invasion and migration, and inhibits cell viability of HCC cells, which
has been proved by several other experiments [
93
].
Brucine, a natural plant indole alkaloid extracted from the dried
seed of Strychnos nux-vomica L. (Loganiaceae), is a traditional medicinal
herb derived from Northern Australia, India, Southeast Asia and South
Asian [
96
,
97
]. It has been con
firmed that brucine possesses various
pharmacological functions, including the e
ffects of anti-angiogenic,
anti-proliferative and anti-tumor. Clinically it is used to relieve swel-
ling, reduce rheumatic pain and treat cancer [
97
,
98
]. Hypoxia in-
ducible factor 1 (HIF1) is a highly conserved transcription factor in
cells, associated with tumor progression involving in cancer cell me-
tastasis and tumor vascularization [
99
,
100
]. Previous research has
suggested that brucine dose-dependently inhibits transactivity of HIF-1
under hypoxia and downregulates expression levels of HIF-1 responsive
genes including
fibronectin, Mmp2, Lox and Ctsd [
100
]. Moreover, an
intraperitoneal injection of brucine can alleviate lung metastasis dose-
dependently in mice with HCC cells [
100
]. Signi
ficant reduction of the
expression of PCNA (a proliferative marker) and VEGF is observed after
brucine treatment [
101
]. Brucine is a dual-acting agent that increases
Glutath thiotransferase (GST) and down-regulates cytochrome P450 to
prevent initiation of N-nitrosodiethylamine (DENA)-induced hepato-
carcinogenesis [
101
]. Supplementally, the expression of Cyclin D1 and
Bcl-2 is reduced, whereas the expression of Bax and Caspase-3 is in-
creased in hepatic tumor, suggesting that the anti-tumor e
ffect of bru-
cine is related to the inhibition of cancer cell proliferation, metastasis,
angiogenesis, and promotion of cycle stagnation and apoptosis.
Another one that has anti-hepatocarcinoma e
ffect and belongs to the
Fig. 4. The main mechanism of isoquinoline alkaloids against liver cancer.
C. Liu, et al.
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