VEGFR-Mediated Cytotoxic Activity of Pulicaria undulata Isolated Metabolites: A Biological Evaluation and In Silico Study

Abstract

Natural products play a remarkable role not only in the synthesis, design, and discovery of new drugs but also as the most prominent source of drugs and bioactive substances. Adding to the search for new sources of safe innovative antitumor drugs, here we reported a phytochemical study on Pulicaria undulata which revealed promising antiangiogenic agents. Six compounds were isolated and identified as xanthoxyline (1), stigmasterol (2), oleanolic acid (3), salvigenin (4), rhamnetin (5) and dihydroquercetin-4′-methyl ether (6) using nuclear magnetic resonance (NMR) spectroscopic techniques. Compound 3 and 4 are first reported in Pulicaria genus. Both the extract and isolated compounds were evaluated for in vitro antiproliferative activity against breast cancer cell line (MCF-7). In vivo antiproliferative activity against Ehrlich’s ascites carcinoma (EAC) were also assessed. The P. undulata extract and isolates showed significant reduction in tumor weight, decreased both serum vascular endothelial growth factor B (VEGF-B) levels and vascular endothelial growth factor receptor 2 (VEGFR-2) expression significantly compared to the control EAC group, suggesting an antiangiogenic activity through the inhibition of VEGF signaling. Besides, they displayed reduction in CD34 expression, confirming their antiangiogenic effect. Moreover, the potential affinity of isolated compounds to human estrogen nuclear receptor-alpha (hER-α), the most recognized modulator of VEGFR-2 expression, was virtually estimated through molecular modeling studies. The most promising activity profiles were assigned to the investigated flavonoids, compounds 4–6, as well as the alkyl-phenylketone, compound 1. Additionally, these four top active compounds showed respective high to intermediate docking scores while possessing preferential binding with hER-α critical pocket residues. Based on the provided data, these isolated compounds illustrated promising inhibitors of VEGF-stimulated angiogenesis, which could be a possible mechanism for their anticancer activity.

Thonningia sanguinea Extract: Antioxidant and Cytotoxic Activities Supported by Chemical Composition and Molecular Docking Simulations

“…In a continuing effort to discover biologically active phytochemicals from medicinal plants [21][22][23][24][25], our group focused on the study of T. sanguinea, a locally well-known medicinal plant widely distributed throughout the forest zones of tropical Africa. T. sanguine is rich in phenolic compounds, such as brevifolin carboxylic acid and gallic acid [26].…”

Polyphenols of the Inuleae-Inulinae and Their Biological Activities: A Review

“…The compound was less cytotoxic against Vero cells (IC50 > 50 μg/mL). In vivo, the flavonol significantly inhibited growth of Ehrlich ascites carcinoma in mice and normalized VEGF level in the serum of the tumor-bearing animals [102]. An expression of the hematopoietic progenitor cell antigen CD34, a marker of angiogenesis, was also significantly reduced in the tumor tissue of the rhamnetin treated mice [102].…”

“…Toxicity of the compound against the noncanceruos Vero (African green monkey kidney) cell line was less pronounced. In vivo, the flavanonol significantly reduced growth of Ehrlich ascites carcinoma in mice and significantly lowered plasma level of vascular endothelial growth factor (VEGF) in tumorbearing animals [102]. (2R,3S)-(-)-4'-O-Methyldihydroquercetin, a compound isolated from Vietnamese B. balsamifera was more potent inhibitor of xanthine oxidase than allopurinol [289].…”

Investigation of Antimicrobial, Anti‐Quorum Sensing, and Cytotoxic Activities of Flavonoids Isolated from Pulicaria armena Boiss. & Kotschy ex Boiss. (Asteraceae)

“…In various nations and cultures, several species of this genus are used as traditional herbal remedies, such as for the treatment of gastritis, colic, back pain, digestive disorders, menstrual cramps, and dysentery, as well as for their wound healing, insect repellent, and anti‐diarrheal properties [1] . It was determined that the chemical constituents of Pulicaria species display a range of carbon skeletons exhibiting substantial bioactivities mainly antimicrobial and cytotoxic [2,3] . Up to date, various secondary metabolites especially phenolic derivatives and characteristic methoxylated flavonoids together with different classes terpenes consist mainly sesquiterpenes (germacranes, xanthanes, pseudoguaianes, guaianes, caryophyllanes and eudesmanes), diterpenes, and triterpenes have been reported from different Pulicaria species [4] …”

“…[1] It was determined that the chemical constituents of Pulicaria species display a range of carbon skeletons exhibiting substantial bioactivities mainly antimicrobial and cytotoxic. [2,3] Up to date, various secondary metabolites especially phenolic derivatives and characteristic methoxylated flavonoids together with different classes terpenes consist mainly sesquiterpenes (germacranes, xanthanes, pseudoguaianes, guaianes, caryophyllanes and eudesmanes), diterpenes, and triterpenes have been reported from different Pulicaria species. [4] Infectious diseases derived from pathogenic bacteria and fungi have posed a substantial risk to human health for ages, leading to a significant amount of morbidity and mortality across the globe.…”