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).