Abstract
Pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea compounds (STIRUR 13, STIRUR 41 and BUR 12) have been demonstrated to exert a strong inhibitory effect on interleukin 8 or N-formyl-methionyl-leucyl-phenylalanine-induced chemotaxis of human neutrophils. Since the migration of cancer cells is comparable to that of neutrophils, the purpose of this study is to evaluate the biological effect of STIRUR 13, STIRUR 41 and BUR 12 on ACN and HTLA-230, two neuroblastoma (NB) cell lines with different degree of malignancy. HTLA-230 cells, stage-IV NB cells, have high plasticity and can serve as progenitors of endothelial cells. The results herein reported show that the three tested compounds were not cytotoxic for both NB cells and did not alter their clonogenic potential. However, all compounds were able to inhibit the ability of HTLA-230 to form vascular-like structures. On the basis of these findings, pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea derivatives could be proposed as agents potentially effective in counteracting NB malignancy by inhibiting cell migration and tumor angiogenesis which represent important hallmarks responsible for cancer survival and progression.
Highlights
Chemotaxis is a complex process which consists of neutrophil migration to the site of inflammation and it is regulated by downstream signaling molecules, including phosphatidylinositol 3-kinase (PI3K), phospholipase C, mitogen-activated protein kinases (MAPKs), and extracellular response kinases 1 and 2 (ERK1/2)
24 h exposure of both NB cell lines to STIRUR 13 (Figure 3A), STIRUR 41 (Figure 3B) and BUR 12 (Figure 3C) did not influence the formation of colonies, supporting the evidence that these compounds were not cytotoxic, as previously observed in neutrophils [1,2,3]. Since these derivatives were reported to limit neutrophil chemotaxis, their capability to interfere with cancer cell migration was investigated
Since pyrazolyl-urea and dihydro-imidazopyrazolyl-urea derivatives have been previously shown to reduce neutrophil migration via the p38MAPK-dependent www.oncotarget.com pathway [1,2,3,4], the aim of this study was to investigate their ability to influence neuroblastoma survival and migration which are demonstrated to be modulated by p38MAPK inhibitors [5, 7]
Summary
Chemotaxis is a complex process which consists of neutrophil migration to the site of inflammation and it is regulated by downstream signaling molecules, including phosphatidylinositol 3-kinase (PI3K), phospholipase C, mitogen-activated protein kinases (MAPKs), and extracellular response kinases 1 and 2 (ERK1/2). In this context, it has been previously demonstrated that pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea compounds, namely STIRUR 13, STIRUR 41 and BUR 12, have a strong inhibitory effect on interleukin-8 STIRUR 13 inhibited only IL-8 induced chemotaxis, whereas STIRUR 41 and BUR 12 were able to block both IL8induced and fMLP-induced neutrophil migration, even though with a different degree of biological activity.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
