angiogenesis, necrosis and mitochondrial
fission, playing an important
role in the development of tumors. The pathways involved in these
phenomena mainly include the Mst1/JNK, PI3K/AKT/mTOR, PTEN/
AKT, Wnt/
β-catenin, FoxO3a/Skp2, PINK1/Parkin axis, AA metabolic
pathway, WWOX pathway, ERK pathway, AMPK pathway, Caspase
pathway etc. (
Fig. 9
).
2.7. Other alkaloids
In fact, there are many alkaloids with anti-tumor e
ffect on the liver.
However, they are not listed in paper because either the research on
those alkloids are insu
fficient or the effect of treating liver cancer is not
remarkable, or they have liver toxicity even causing liver cancer
themselves. For instance, pyrrolizidine alkaloids are a classic example.
Pyrrolizidine alkaloids (PAs) are common phytotoxins found in more
than 6000 plant species worldwide. Previous studies have shown that
PAs trigger apoptosis in liver cells and its intoxication can lead to severe
liver damage [
137
]. PAs can be brought into the body due to food
contamination. In 1954, retrorsine (a pyrrolizidine alkaloid) was in-
dicated to induce liver tumors in rats, and until 2001, riddelliine (a
tumorigenic pyrrolizidine alkaloid), was found to induce liver tumors
through a genotoxic mechanism mediated by ( ± )-6,7-dihydro-7-hy-
droxy-1-hydroxymethyl-5H-pyrrolizine (DHR)-derived DNA adduct
formation [
138
,
139
]. Acute PAs toxicosis induces severe liver damage,
and prolonged exposure to sub-lethal doses may generate accumulative
damage or hepatic cirrhosis or cancer [
140
]. Proteins and alkylation of
DNA are considered to be one molecular mode of action regarding the
hepatotoxicity of PAs. Besides, molecular mechanisms such as interac-
tions with molecular targets and speci
fic cellular, and subsequent dys-
regulation of cellular signaling and metabolic pathways, may also play
a large role in disrupting cell balance, hence leading to hepatotoxicity
[
140
]. It is well known that intracellular metabolism can generate
genotoxicity, thus intake of PAs-comprising products is a major cause of
hepatic sinusoidal obstruction syndrome (HSOS), also known as hepatic
veno-occlusive disease (HVOD) [
141
]. The clinical manifestations of
HSOS are painful hepatomegaly, ascites formation, severe progression
to cirrhosis, etc. PAs-induced intoxication is associated with a lack of
energy metabolism and the depletion of glutathione. It is found that two
proteins, CPS1 (carbamoyl-phosphate synthase) and ATP5B (ATP syn-
thase subunit beta) as well as their associated pathways including urea
cycle and mitochondria dysfunction, play crucial roles in the initiation
of HSOS [
141
].
Acridone alkaloids are also a class of natural products mainly from
Swinglea glutinosa (Rutaceae) which display selective cytotoxicity
against prostate, lung, breast, liver human carcinoma cells lines [
142
].
It is shown that acridone alkaloids possess various pharmacological
activities including antibacterial, antifungal, anti-in
flammatory, in-
hibitory smooth muscle relaxant, antiulcer, anxiolytic, insecticide and
diarrhea [
142
]. The researcher has isolated several acridone alkaloids
including
natsucitrine-I,
5-hydroxynoracronycine,
11-hydro-
xynoracronycine, citrusinine-I, glycofolinine, citracridone-I and ci-
tracridone-III from the DCM fraction of C. aurantium. It is noteworthy
that the isolated compounds exert cytotoxicity at least four times more
selective towards the carcinoma cells than the normal human prostate
epithelium cells(PNT2), showing the least activity on HepG2 cells
(IC
50
= 5.73
μg/mL) and the highest activity against A549 cells
(IC
50
= 3.88
μg/mL) [
142
]. The anti-hepatocarcinogenic activity of
acridone alkaloids and their extracts have been re
flected in HepG2
Human liver hepatocellular carcinoma and Hep3B Human hepatoma
[
143
]. However, the detailed mechanism of acridone alkaloids against
liver cancer is rarely reported in the literature. Several researchers have
designed and synthesized a series of multi-substituted benzyl acridone
Fig. 9. The mechanism of alkaloids against liver cancer.
C. Liu, et al.
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