Crocetin and Its Glycoside Crocin, Two Bioactive Constituents From Crocus sativus L. (Saffron), Differentially Inhibit Angiogenesis by Inhibiting Endothelial Cytoskeleton Organization and Cell Migration Through VEGFR2/SRC/FAK and VEGFR2/MEK/ERK Signaling Pathways

Abstract

Crocetin and crocin are two important carotenoids isolated from saffron (Crocus sativus L.), which have been used as natural biomedicines with beneficial effects for improving the suboptimal health status associated with abnormal angiogenesis. However, the anti-angiogenic effects and underlying mechanisms of the effects of crocetin and crocin have not been investigated and compared. The anti-angiogenic effects of crocetin and crocin were tested on human umbilical vein endothelial cells (HUVECs) in vitro, and in zebrafish in vivo. In vivo, crocetin (20 μM) and crocin (50 and 100 μM) significantly inhibited subintestinal vein vessels formation, and a conversion process between them existed in zebrafish, resulting in a difference in their effective concentrations. In the HUVEC model, crocetin (10, 20 and 40 μM) and crocin (100, 200 and 400 μM) inhibited cell migration and tube formation, and inhibited the phosphorylation of VEGFR2 and its downstream pathway molecules. In silico analysis further showed that crocetin had a higher ability to bind with VEGFR2 than crocin. These results suggested that crocetin was more effective than crocin in inhibiting angiogenesis through regulation of the VEGF/VEGFR2 signaling pathway. These compounds, especially crocetin, are potential candidate natural biomedicines for the management of diseases associated with abnormal blood vessel growth, such as age-related macular degeneration.

Crocin molecular signaling pathways at a glance: A comprehensive review

“…Dysregulation in VEGF signaling could be related to pathologic conditions, such as rheumatoid arthritis and age‐related macular degeneration (Kowanetz & Ferrara, 2006). Zhao et al (2021) with in vitro and in vivo studies demonstrated the angiogenesis inhibitory effect of crocin exerted through VEGF signaling pathway inhibition. Crocin inhibited VEGF expression and may be helpful as an attractive alternative option for cancer treatment, including breast cancer (Farahi et al, 2021; Saravani et al, 2020) and melanoma (Bakshi et al, 2018).…”

Antibiofilm activity of carotenoid crocetin against Staphylococcal strains

“…Crocetin, categorized as a lipophilic carotenoid, contrasts with crocin, which serves as the hydrophilic diester of crocetin combined with gentiobiose ( Zhao et al., 2021 ). While crocetin demonstrated robust antibiofilm activity against staphylococcal strains and exhibited antibacterial effects at relatively high concentrations, crocin, on the other hand, proved ineffective in displaying antibiofilm or antibacterial properties ( Figures 1 , 2 ).…”

Anti-Depressant Properties of Crocin Molecules in Saffron

“…Crocetin ( Figure 1 B) and crocins were shown to inhibit in vivo and in vitro angiogenesis, with crocetin being more effective [ 66 ]. Thus, crocetin could possibly be employed to retard abnormal blood vessel growth.…”