Selenadiazole Derivatives Inhibit Angiogenesis‐Mediated Human Breast Tumor Growth by Suppressing the VEGFR2‐Mediated ERK and AKT Signaling Pathways

Abstract

Selenadiazole derivatives (SeDs) have been found to show promise in chemo-/radiotherapy applications by activating various downstream signaling pathways. However, the functional role of SeDs on angiogenesis, which is pivotal for tumor progression and metastasis, has not yet been elucidated. In the present study, we have examined the antiangiogenic activities of SeDs and elucidated their underlying mechanisms. The results showed that the as-synthesized SeDs not only enhanced their anticancer activities against several human cancer cells but also showed more potent inhibition on human umbilical vein endothelial cells (HUVECs). The in vitro results suggested that SeDs, especially 1 a, dose-dependently inhibited the vascular endothelial growth factor (VEGF)-induced cell migration, invasion, and capillary-like structure formation of HUVECs. Compound 1 a also significantly suppressed VEGF-induced angiogenesis in a Matrigel plug assay as part of a C57/BL6 mice assay by means of down regulation of VEGF. Furthermore, we found that 1 a significantly inhibited MCF-7 human breast tumor growth in nude mice without severe systematic cytotoxicity. Compound 1 a was more effective in inhibiting cell proliferation and induced a much more pronounced apoptosis effect in endothelial cells than MCF-7 cells, which implies that endothelial cells might be the primary target of 1 a. Further mechanistic studies on tumor growth inhibition effects and neovessel formation suppression demonstrated that 1 a inhibited cell viability of MCF-7 and HUVECs by induction of cell apoptosis, accompanied by poly(adenosine diphosphate ribose)polymerase (PARP) cleavage and caspase activation. Additionally, the 1 a-induced antiangiogenesis effect was achieved by abolishing the VEGF-VEGFR2-ERK/AKT (ERK=extracellular signal-regulated kinases; AKT=protein kinease B) signal axis and enhanced the apoptosis effect by triggering reactive oxygen species (ROS)-mediated DNA damage. Taken together, these results clearly demonstrate the antiangiogenic potency of SeDs and the underlying molecular mechanisms.

Chemosensitization of doxorubicin against lung cancer by nature borneol, involvement of TRPM8-regulated calcium mobilization

“…Similar to ROS, when the intracellular calcium exceeds a certain threshold, it may in turn inhibit the p44/p42-MAPK pathway leading to crosstalk between other signaling pathways. In addition, studies have shown that MAPK and AKT are the main oxidative stress sensitive signal transduction pathways [25]. Consistent with reported studies, we found that DOX can activate p38MAPK and JNK signals [46].…”

“…A549 cells and NCM460 cells were purchased from ATCC (Manassas, VA) and cultured according to manufactory's instruction. After pretreated with NB for 12 h, different doses of chemotherapy agents were added and cocultured for 72 h. Cell viability was determined by MTT assay according to previous publications [25].…”

Iron(II)−Polypyridyl Complexes Inhibit the Growth of Glioblastoma Tumor and Enhance TRAIL‐Induced Cell Apoptosis

“…[34] Western Blot Assay AWestern blot assay was used to determine the changes in the expression levels of the proteins after treatment with the iron complexes and TRAIL, according to al iterature procedure. [35]…”

Development and Therapeutic Potential of Selenazo Compounds

“…123 p-Methylbenzaldehyde derived selenadiazole also showed breast cancer tumor growth inhibition in murine model, due to antiangiogenic effect, as reflected by a greater growth inhibition of endothelial cells HUVEC in Matrigel plug assays. 133 2-Indol-3-ylbenzimidazol-6-yl derivative was conjugated to a cyclic peptide containing RGD sequence, able to target αVβ3 integrin. 134 Taking advantage of fluorescent properties of the compound, improved cellular uptake of integrin-overexpressing cancer cells (HepG2) could be confirmed, thus enhancing the effectiveness of radiotherapy in vitro and reproducibility in vivo.…”