4. Antiangiogenic effects onnovel derivatives of
aspirin and ATL-1
Some less serious adverse events of aspirin are involved in stomach
pain, vomiting, nausea and heart-burn (Hua et al., 2019). Long-term
aspirin therapy may induce gastrointestinal injury. Even low-dose
aspirin can damage the gastroduodenal mucosa in varying degrees,
including ulcers, erosions, and bleeding (Lavie et al., 2017). Another
adverse event of aspirin is aggravating respiratory diseases such as
asthma and chronic sinusitis with nasosinusal
polyposis (Pavón-Romero et al.,
2017). Thus, in order to become greater safety and greater efficacy
compared with ASA, the new derivatives of aspirin are needed.
The NO-donating non-steroidal anti-inflammatory drugs are expected to
bring these two promising features for cancer prevention and treatment
relative to traditional similar drugs (Yeh et al., 2004; Rigas et al.,
2007). For NO-releasing aspirin, NO itself could induce COX2 expression
(Basudhar et al., 2017), but aspirin may inhibit it thereby neutralizing
the harmful effect of NO. In that way, it is expected that novel
derivative of NO-releasing aspirin might show less gastrointestinal
injury than aspirin. It has been demonstrated that NO-donating aspirin
supresses tumor angiogenesis by inhibiting VEGF expression and reducing
the microvessel density in cancer mice xenografts (Ouyang et al., 2008).
PGE2 as a downstream mediator play a major role in regulating
angiogenesis, and suppression of its formation is involve in
antiangiogenic effects (Méric et
al., 2006). Co-ASS, Co2(CO)6 alkyne
derivatives of aspirin (Co–aspirin), significantly inhibited cellular
PGE2 formation from arachidonic acid in breast tumor
cells (Ingo et al., 2009). Besides, the zebrafish embryos, an
established model organism for studying angiogenesis and vascular
development, treat with Co-ASS showed severe defects in angiogenesis,
which is manifested in the lack or impaired formation of dorsal
longitudinal anastomotic vessels and intersegmental vessels, as well as
the reduction of intestinal veins (Lawson et al., 2002; Ott et al.,
2009).
Moreover, aspirin-PC is another derivative of aspirin in which
PC-enrichedsoylecithin is formulated with aspirin. In short-term
clinical trials, the development of PC-related aspirin has been proved
to be less harmful to the gastroduodenal mucosa because of its ability
to protect the hydrophobic barrier property of the tissue surface (Cryer
et al., 2011). Previous study demonstrate that treatment with aspirin-PC
significantly reduce the level of VEGF and the number of tumor
microvessels in ovarian tumor tissue, especially when aspirin-PC is used
in combination with bevacizumab (Huang et al., 2016).
It has been shown that, when COX-2
acetylated by aspirin, the ability of generating prostanoids is blocked,
yet acetylized COX-2 remains active in epithelial cells, mononuclear
cells and endothelial cells and initiates the biosynthesis of new
product of transcellular biosynthesis or cell-cell interactions termed
as aspirin-triggered-15-epi-lipoxins (ATLs) (Clària et al., 1995). The
previously studies reveal that 15-epi-16-(para-fluoro)-phenoxy-lipoxin
A4 (ATL-1), an ATLs stable analog, inhibited VEGF-stimulated endothelial
cell proliferation and migration in a concentration-dependent manner
(Fierro et al., 2002). Moreover, VEGF-driven HUVEC migration requires
the synergistic activation of two complementary pathways: one pathway
involves the activation of SAPK2/p38 MAP kinase-mediated actin, and the
other involves the phosphorylation of focal adhesion kinase (FAK) and
the assembly of focal adhesions (Rousseau et al., 2000). Treatment of
HUVEC with ATL-1 significantly reduced VEGF-induced p38 and FAK
phosphorylation (Cezar-de-Mello et al., 2006). Besides, the multiple
steps in the angiogenesis process also inhibited by ATL-1, including
VEGF-induced EC proliferation, MMP-9 activity, HUVEC adhesion and
VEGFR-2 phosphorylation (Cezar-de-Mello et al., 2008).