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Chen et al. Hepatoma Res 2018;4:29 I http://dx.doi.org/10.20517/2394-5079.2018.18 Page 9 of 15

of Bel-7402 cells through periodic blockade . The process involves mainly involved in MAPK, Wnt, Hippo
[120]
and PI3K-Akt/mTOR signaling pathways . Quercetin can enhance the antiproliferative effect of IFN-α in
[121]
hepatocarcinoma cells by inhibiting SHP2 phosphatase activation of JAK/STAT signaling pathway . The
[122]
results showed that quercetin nanoparticles could inhibit caspase/Cyto-c signaling pathway, inhibit AP-2
and NF-κB, block Akt/ERK signaling pathway to play an antitumor effect . Genistein can induce HCC cell
[123]
death by regulating the inhibition of aerobic glycolysis by HIF-1α, and genistein can regulate gene products
Cyclin D1, Bcl-xL, Bcl-2, c-myc and COX-2 by inhibiting NF-κB and VEGF expression, and then alleviate
the occurrence and development of HCC .
[124]

Myrtenal is an important variety of spices, has been widely used in daily chemical, pharmaceutical, food and
other industries. Studies have shown that, as a natural monoterpene, Myrtenal can inhibit DEN-induced high
expression of TNF-α in HCC . Myrtenal also improves DEN-induced hepatocarcinogenesis by activating
[125]
tumor suppressor protein p53 and modulating lysosomal and mitochondrial enzymes .
[125]
Hesperidin is a chalcone compound. Many articles have reported that it has a good anti-liver cancer effect
was shown through the Wnt pathway, ROS, ATP and calcium [126-128] . More importantly, hesperidin on tumor
cell invasion inhibition was realized mainly through inhibition of AP-1 and NF-κB in human HCC cells .
[129]

Synthetic anti-inflammatory agents
Aspirin is a clinical analgesic and antipyretic drug. Due to its long clinical application and high safety,
research on its multiple clinical conditions is now receiving great attention. At present, studies have shown
that aspirin has good anti-tumor activity . Among them, the application of liver cancer has been gradually
[130]
reflected. A large number of clinical studies have shown that long-term use of aspirin in HCC patients can
inhibit the expression of AMPK, mTOR and β-catenin and thus inhibit the progress of liver cancer .
[131]
Our recent study suggested aspirin as a promising chemopreventive and chemotherapeutic agent for liver
cancer. There is a current prospective randomized controlled trial registered in China to investigate the
effect of sorafenib combined with aspirin in preventing patient risk for postoperative surgical recurrence
of HCC (NCT02748304). We have demonstrated that by combining low-dose sorafenib and aspirin, the
synergistic antitumor effects observed are related to the simultaneously silencing of ACSL4 and the
induction of GADD45B expression. The clinical survival of HCC patients expressing ACSL4 GADD45
high
low
high
was significantly poorer compared to patients with ACSL4 GADD45B expression, thus demonstrating
low
the potential clinical value of combining aspirin and sorafenib to treat HCC patients expressing
ACSL4 GADD45 low[132] .
high
There are so many special COX2-inhibitors, like celecoxib, etodolac, JTE-522 and nimesulide. Even
though those are COX-2 inhibitors, their principles of pharmacological activity are different. Celecoxib
inhibited the translocation of p65 to the nucleus from the cytoplasm [133] . R-Etodolac (at physiological
doses) and Celecoxib (at high concentrations) on HCC cells were accompanied by the down-regulation
of β-catenin [134] . CDAA model activated hepatic stellate cells and promoted CD45-positive inflammatory
cells coming in the liver. JTE-522 can attenuate all the change [135] . Nimesulide inhibits the proliferation
[136]
of HepG2 by up-regulation of Smad4 and downregulation of HSP70 gene expression of SMMC-7721 .
Roxithromycin is a new generation of macrolide antibiotics. It inhibits constitutive activation of NF-κB
by diminishing oxidative stress or suppressing VEGF production in a rat model of HCC [137] . Erlotinib, a
special EGFR inhibitor, involves in development of HCC. It is reported that EGFR-ERK pathway has been
inhibited by erlotinib in HCC model [138] . However, due to extensive use of erlotinib, some patients with
HCC in clinical trials have become resistant. Therefore, the study turned to combination therapy [139-141] .
In the literature, neurotensin regulation induces overexpression and activation of EGFR in HCC and
restores response to erlotinib [142] .