| 其他摘要 | Liver cancer is a serious health problem, with more than 700,000 new cases
diagnosed worldwide annually. Liver cancer is one of the most common malignancies,
accounting for about 6% of all human cancers and one million deaths worldwide each
year. Although the prognosis of patients with a surgically-resectable localized tumor is
better, the five-year survival rate of patients with liver cancer is only 30-40%.
Therefore, there is an urgent need to find novel treatment strategies for liver cancer.
Sorafenib (multikinase inhibitor) is the only drug approved by the FDA for the
treatment of advanced liver cancer. It has been reported that sorafenib could display
significant anti-hepatocellular carcinoma (HCC) activity through inhibiting tumor cell
growth and angiogenesis. However, the severe side effects of sorafenib, including
diarrhea, nausea and skin toxicity, severely lower the life quality of patients and limit
its therapeutic efficacy in clinical use. Acquired drug resistance to sorafenib has been
severely hampering its applications during treatment of HCC. One approach for
reducing the toxicity and drug resistance of sorafenib is to use lower doses of
sorafenib in combination with other anti-HCC agents. That is to say, to develop a
cocktail of anti-HCC drugs.
To obtain active substances with good anti-HCC activiy and acting
synergistically with sorafenib in the inhibition of HCC, screening from libraries of
seaweed polysaccharides, Ganoderma compounds, and marine microbial
exopolysaccharides was conducted in our study. And we screened a novel
polysaccharide from Sargassum integerrimum (SPS170), a triterpenoid from
Ganoderma lucidum (GL22) and an exopolysaccharide from marine Vibrio
alginolyticus (EPS364). The molecular mechanisms of the growth inhibition on
Huh7.5 cells in vitro were studied in our research.
Our results show that sorafenib causes mitochondrial damage, desearse of ATP
production, activation of the ATP-AMPK-mTOR-SREBP1 pathway, down-regulation
of SCD1 expression, reduction of monounsaturated fatty acid contents, and finally
growth inhibition and cell death in Huh7.5 cells. SPS170 significantly reduces Huh7.5
cells viability in a dose- and time-dependent manner. SPS170 induces cell apoptosis,
the loss of mitochondrial membrane potential (MMP), and generation of reactive
oxygen species (ROS). Up-regulation of the expression of P53, increase in the ratio of
Bax/Bcl-2, and activation of cleaved caspase-3, caspase-9 and PARP are also detected
after the treatment of SPS170. In addition, SPS170 inhibits the proliferation,
migration and cord formation of human umbilical vein endothelial cells (HUVECs) in
vitro, and prevents the vascular development of zebrafish embryos in vivo. GL22
displays robust antitumor activity against Huh7.5 cells in vitro and in vivo. GL22
affects PPAR-FABPs pathway and inhibits the expression of FABPs, leading to
disrupted FA transport, reduced cardiolipin synthesis, mitochondrial dysfunction and
cell death. EPS364, isolated from the Vibrio alginolyticus 364, significantly inhibits
the proliferation of Huh7.5 cells, induces cell aggregation and disappearance of
filiform structures. ECM-receptor and cell adhesion molecules signaling pathways are
those that change significantly in GL22-treated Huh7.5 cells.
Anti-HCC drugs cocktail therapy is a combination of two or more drugs that
target the HCC in different ways and act synergistically in the inhibition of HCC. On
the one hand, it potentiates the therapeutic effects of these drugs on HCC and reduces
the drug dosage. On the other hand, it significantly lowers the serious side effects of
high-dose drugs and improves the life quality of patients. The development of
anti-HCC drugs cocktail therapy will play an important role in treatment of HCC in
the future. Our research will provide theoretical basis for future development of
anti-HCC drugs cocktail therapy. |
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