6063 In addition to FAK P MAPK

In addition to FAK, P-38 MAPK (38 kDa polypeptide) serves as cross-talk effector for signal transduction, enabling this factor to play a vital role in numerous biological processes (Cuenda and Rousseau, 2007). Pharmacologically modulation of P-38 has shown to be an effective approach in the orientation of target 6063 to mimic desired behavior (Aggarwal and Sung, 2009). From past to present, many phyto-compounds are found to have pro- and anti-angiogenesis capacity (Sofi and Nabi, 2018; Albini et al., 2018). Curcumin, a natural polyphenol extracted from turmeric (Curcuma longa), is not toxic to human (Fig. 1) (Akram et al., 2010). Curcumin has been used as medicinal plant for years in Orient as a healing agent for variety of diseases (Nagpal and Sood, 2013). Numerous biological activates such as anti-oxidative, anti-inflammatory, anti-septic and anti–tumoral properties are commonly implied in the scientific literature (Noorafshan and Ashkani-Esfahani, 2013; Liu and Chen, 2013). Curcumin is able to inhibit the cell survival and decrease angiogenesis and migratory properties through engaging the apoptosis signaling pathways (Bimonte et al., 2013; Bandyopadhyay, 2014). In addition, the modulation of various cell signaling pathways, transcription factors, protein kinases, growth factors, and different enzymes activity proved after exposure to curcumin (Bimonte et al., 2013).
Materials and methods
Results
Discussion The current experiment aimed to investigate the anti-angiogenic effect of curcumin by the modulation of FAK/P-38 MAPK signaling pathway in vitro. Curcumin is a polyphenol compound derived from Curcuma longa that has anti-inflammatory effects, inhibition proliferation, angiogenesis, invasion, and metastasis (Leite et al., 2009). The results from survival assays showed the reduction of HUVECs exposed to curcumin in a dose-dependent manner after 72 h. Consistent with our data, most studies demonstrated a significant decrease in the cell survival by engaging different intracellular mechanisms. For example, it was found that curcumin had potential to inhibit laryngeal cancer cells dynamic growth and increase the number of cells entering apoptosis by suppressing Bcl-2 and PI3K protein expression, reduction of p-Akt/Akt ratio and induction of caspase-3/7 activity (Mou et al., 2017; Fu et al., 2015). Fu and coworkers previously showed that curcumin is able to induce cytotoxicity in the endothelial lineage of HUVECs through down-regulation of VEGF receptors and pathways related to RTKs (Fu et al., 2015). Another finding to the current experiment was an inhibited tubulogenesis and migration in HUVECs exposed to curcumin for 72 h. In line with our results, Hahm and coworkers showed that curcumin and its derivatives could inhibit the transcription of AP-1and MMP-9 expression. Both factors are thought to be essential in the process of tumor angiogenesis (Hahm et al., 2004). In addition, the stimulatory effect of VEGF on prostaglandin E2 production and cyclooxygenase-2 was suppressed following human intestinal microvascular ECs exposure to curcumin, resulting in a reduced migration rate and tubulogenesis activity (Binion et al., 2008). Monitoring the expression of VEGF for 24 h after treatment with curcumin revealed an increase in transcription level. It seems that the expression of VEGF depends on time and dose of curcumin. In some experiments, the inhibitory effect of curcumin was proved on the inhibition of VEGF (Fu et al., 2015; Gururaj et al., 2002). The reason for a discrepancy related to the effect of curcumin on VEGF in the current experiment and previous studies could be correlated with the incubation period. Most of the experiment confirmed the inhibitory effect of curcumin after 48 h and/or longer time periods. Our results indicated that curcumin inhibited P-38 activity in a time-dependent manner at 50 μM. Consistent with our results, Binion and coworkers demonstrated that curcumin inhibits the activation of MAPKs (P44/42 MAPK, P38MAPK, and JNK) in VEGF-induced human intestinal microvascular ECs (Binion et al., 2008). To confirm whether curcumin inhibits the activation of MAPKs in VEGF-activated HIMECs, these cells were pretreated with curcumin and were then stimulated by VEGF. Phosphorylation of MAPKs by VEGF was significantly decreased by curcumin pretreatment of human intestinal microvascular ECs. These results indicate that curcumin attenuates VEGF-induced effects through the inhibition of MAPK pathways.