Novel coumarin derivatives containing a triazole moiety: A study on synthesis, cytotoxicity, membrane dysfunction, apoptosis, cell cycle, and antiangiogenic studies

Background: Coumarin is a functional compound with a pronounced wide range of biological activities and has recently been shown to have anticancer effects on various human cancer cells. Cisplatin is widely used in treating many cancers, but its effectiveness is limited due to acquired resistance and dose-related side effects. Objective: This study aimed to reveal the chemosensitizing ability of novel synthesized coumarin-triazole hybrid compounds (3a-f) compared to the cisplatin in A549, MCF-7, and HeLa cancer cells. Methods: Cytotoxicity was determined by MTT assay. Lactate dehydrogenase (LDH), antioxidant/oxidant status, DNA fragmentation were determined spectrophotometrically using commercial kits. Muse™ Cell Analyzer was used to assess cell cycle progression. Pro/anti-apoptotic gene expressions were determined by Real-Time qPCR. The antiangiogenic activity was determined by VEGF expression and Hen's chorioallantoic membrane model. Results: Compounds 3c, -d, -e, and -f potentiated the cisplatin-induced cytotoxicity through the increased LDH release and DNA fragmentation, induced G2/M cell cycle arrest, overproduction of oxidative stress, and decrease of cellular antioxidant levels. These compounds combined with cisplatin caused upregulation in the pro-apoptotic Bax, Bıd, caspase-3, caspase-8, caspase-9, Fas, and p53 gene expressions while downregulating anti-apoptotic DFFA, NFkB1, and Bcl2 gene expressions. These combinations caused vascular loss and a reduction in VEGF expression. Conclusion: These results suggest that a combinational regimen of coumarin compounds with cisplatin could be enhancing the effect of cisplatin in A549 cells. Besides, considering compounds have relatively low toxicity in normal cells, they decrease the dose requirement of cisplatin in cancer treatments.

Association Between DCE-MRI Perfusion Histogram Parameters and EGFR and VEGF Expressions in Different Lauren Classifications of Advanced Gastric Cancer

Objective: To investigate the correlations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion histogram parameters and vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions in advanced gastric cancer (AGC).Methods: This retrospective study included 80 pathologically confirmed patients with AGC who underwent DCE-MRI before surgery from February 2017 to May 2021. The DCE-MRI perfusion histogram parameters were calculated by Omni Kinetics software in four quantitative parameter maps. Immunohistochemical methods were used to detect VEGF and EGFR expressions and calculate the immunohistochemical score.Results: VEGF expression was relatively lower in patients with intestinal-type AGC than those with diffuse-type AGC (p < 0.05). For VEGF, Receiver operating characteristics (ROC) curve analysis revealed that Quantile 90 of Ktrans, Meanvalue of Kep and Quantile 50 of Ve provided the perfect combination of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for distinguishing high and low VEGF expression, For EGFR, Skewness of Ktrans, Energy of Kep and Entropy of Vp provided the perfect combination of sensitivity, specificity, PPV and NPV for distinguishing high and low EGFR expression. Ktrans (Quantile 90, Entropy) showed the strongest correlation with VEGF and EGFR in patients with intestinal-type AGC (r = 0.854 and r = 0.627, respectively); Ktrans (Mean value, Entropy) had the strongest correlation with VEGF and EGFR in patients with diffuse-type AGC (r = 0.635 and 0.656, respectively).Conclusion: DCE-MRI perfusion histogram parameters can serve as imaging biomarkers to reflect VEGF and EGFR expressions and estimate their difference in different Lauren classifications of AGC.

Expression of Vascular Endothelial Growth Factor in Uveal Melanoma

A prerequisite for the growth, progression and metastasis of malignant tumors of any localization is the development of its own vascular network. Newly formed vessels not only nourish the primary tumor, but also create conditions for the spread of tumor cells through the circulatory system and the formation of distant metastases. Angiogenesis is able to launch a small population of tumors from 100–300 cells that have accumulated genetic aberrations and have begun to express proangigenic molecules. The phenomenon is known as “transformation of tumor cells into angiogenic phenotype”. A tumor with angiogenic phenotype carries a high potential for proliferation and malignization. This pattern has been found in many types of cancer, but studied less in uveal melanoma. Meanwhile, in this aspect, uveal melanoma, metastasizing exclusively in a hematogenic way, with its selective, organotropic nature of metastasis, becomes an attractive model for the study of the molecular “scenario” of tumor angiogenesis studies allow us to say that, UM is subject to the general patterns of the development of malignant tumors. As with many types of tumors, VEGF is an obligate condition for the development and progression of UM. The VEGF molecule’s producers in UM are two cell populations: endothelial vascular cells and tumor cells. VEGF’s expression in UM is cyclical. The cycle is re-initiated, apparently, by increasing cell density in tumor proliferate and the development of hypoxia zones. We found no correlation between the intensity of pigmentation, necrosis, hemorrhage, germination in the corner of the front chamber, ophthalmohypertension on the one hand, and expression of VEGF in UM cells on the other. At the same time, a direct link between the expression of VEGF in tumor cells and EC vessels on the one hand and the thickness, base diameter, as well as the localization of UM, on the other hand, has been revealed. Additionally, VEGF expression in tumor cells was closely correlated with the histological structure of UM, and VEGF expression in EC correlated with the stage of the disease. Thus, the authors showed that UM, like other malignant solid tumors, is prone to transformation into angiogenic phenotype and expression of VEGF.

VEGF Modulates Neurogenesis and Microvascular Remodeling in Epileptogenesis After Status Epilepticus in Immature Rats

Neurogenesis and angiogenesis are widely recognized to occur during epileptogenesis and important in brain development. Because vascular endothelial growth factor (VEGF) is a critical neurovascular target in neurological diseases, its effect on neurogenesis, microvascular remodeling and epileptogenesis in the immature brain after lithium-pilocarpine-induced status epilepticus (SE) was investigated. The dynamic changes in and the correlation between hippocampal neurogenesis and microvascular remodeling after SE and the influence of VEGF or SU5416 injection into the lateral ventricles at different stages after SE on neurogenesis and microvascular remodeling through regulation of VEGF expression were assessed by immunofluorescence and immunohistochemistry. Western blot analysis revealed that the VEGFR2 signaling pathway promotes phosphorylated ERK and phosphorylated AKT expression. The effects of VEGF expression regulation at different stages after SE on pathological changes in hippocampal structure and spontaneous recurrent seizures (SRS) were evaluated by Nissl staining and electroencephalography (EEG). The results showed that hippocampal neurogenesis after SE is related to microvascular regeneration. VEGF promotion in the acute period and inhibition in the latent period after SE alleviates loss of hippocampal neuron, abnormal vascular regeneration and inhibits neural stem cells (NSCs) ectopic migration, which may effectively alleviate SRS severity. Interfering with VEGF via the AKT and ERK pathways in different phases after SE may be a promising strategy for treating and preventing epilepsy in children.

The role of vascular endothelial growth factor as a prognostic and clinicopathological marker in osteosarcoma: a systematic review and meta-analysis

Background In recent years, numerous investigations have been conducted to determine the clinical significance and critical functions of vascular endothelial growth factor (VEGF) in various malignant cancers. The purpose of this meta-analysis was to comprehensively evaluate the prognostic and clinicopathological value of VEGF in patients with osteosarcoma. Methods We performed a systematic literature retrieval of available databases. Odds ratios (ORs) or standard mean difference (SMD) for clinicopathological parameters, hazard ratios (HRs) for overall survival and disease-free survival were calculated to assess the correlation between VEGF expression and prognosis in patients with osteosarcoma. Results A total of 22 studies with 1144 patients were included in our study. Pooled analyses showed that VEGF overexpression predicted worse overall survival (HR, 2.42; 95% CI, 1.87–3.11, p < 0.001) and disease-free survival (HR, 2.604; 95% CI, 1.698–3.995, p < 0.001), respectively. Furthermore, investigation regarding osteosarcoma clinicopathologic characteristics suggested that high VEGF expression was significantly associated with metastasis (OR, 4.39; 95% CI, 2.77–6.95; p < 0.001), clinical stage (OR, 0.73; 95% CI, 0.62–0.87; p < 0.001), and microvessel density (SMD, 3.33, 95% CI,1.57–5.10, p < 0.001), but not associated with tumor location, gender, age, local recurrence, and chemotherapy response. Conclusion Our meta-analysis findings suggest that elevated VEGF expression may be a predictive biomarker for poor prognosis and adverse clinicopathological characteristics in patients with osteosarcoma.