Rosmarinic Acid Inhibits Cell Growth and Migration in Head and Neck Squamous Cell Carcinoma Cell Lines by Attenuating Epidermal Growth Factor Receptor Signaling

Abstract

Objective: Active components of natural foods are increasingly receiving attention for their chemopreventive and chemotherapeutic potential in a wide variety of cancers. Rosmarinic acid (RA), a phenolic compound in various herbal plants, is well-recognized for its anti-oxidant, anti-inflammatory, anti-proliferative properties in a variety of cell types. In this report, we describe a novel role for RA as an inhibitor of epidermal growth factor (EGF) stimulated signaling in HNSCC and propose a cellular reactive oxygen species (ROS)-mediated mechanism for the observed effects.Methods: Cellular growth, migration and reactive oxygen species (ROS) profiles were examined in RA-treated and untreated HNSCC cell lines (UM-SCC-6 and UM-SCC-10B) using the WST-1 viability assay, established in vitro migration assays, and the CM-H2DCFDA ROS assay, respectively. The influence of RA on EGF-stimulated phosphorylation and its downstream pathways was evaluated using Western-blotting techniques.Results: RA inhibited cell viability, migration and cellular production of ROS in HNSCC cell lines. Furthermore, RA inhibited EGF-induced phosphorylation of the EGFR at tyrosine residues 992 and 845, which led to downregulation of the phosphatidylinositol 3-kinase Akt (PI3K/Akt) and mitogen-activated protein kinase ERK (MAPK/ ERK) pathways.Conclusions: This is the first report describing both growth-and motility-inhibitory roles for RA in HNSCC cells. Additionally, our study is the first to demonstrate that treatment with RA can reduce EGF-induced activation of PI3K/ Akt in tumor cells. The present data suggests that RA holds promise as a chemotherapeutic agent against HNSCC. a novel strategy to down-regulate EGFR signaling using the phenolic compound, rosmarinic acid. RosmarinicActive components of natural foods are increasingly receiving attention for their chemopreventive and chemotherapeutic potential in a wide variety of cancers. One such food component, rosmarinic acid (RA), is a widely distributed phenolic compound in various herbal plants such as rosemary, sweet basil, sage, mint, and perilla (Figure 1) [10,11]. RA is regarded as a daily-consumed safe ingredient, due to its extensive use in the food industry for flavoring, but studies have also elucidated a medicinal role for RA, especially in regard to its anti-oxidant, and anti-inflammatory activities [12,13]. Furthermore, an emerging body of literature has also described the growth inhibitory and anti-invasion properties of RA in colon, skin, breast and ovarian cancers in vitro and/or in vivo [14][15][16][17][18][19], but the mechanisms underlying these effects are poorly understood. A chemopreventive role for RA in HNSCC has been described in 7,12-dimethylbenz (a) anthracene-induced hamster buccal pouch carcinogenesis [20], but a chemotherapeutic role for RA in the treatment of HNSCC has not yet been reported.Given the anti-oxidant properties attributed to RA, it is possible that RA's anti-tumor effects stem from its ability to combat oxidative stress in HNSCC. Oxidative ...

Rosmarinic acid and siRNA combined therapy represses Hsp27 (HSPB1) expression and induces apoptosis in human glioma cells

“…*P < 0.05, **P < 0.01, ***P < 0.001 determined by one-way ANOVA using Dunnet's multiple comparison test. C control, Q quercetin, RA rosmarinic acid, si siRNA cell carcinoma cell lines by inhibiting EGFR phosphorylation and MAPK signaling (Tumur et al 2015). We demonstrated in this study that RA treatment reduces Hsp27 expression and induces caspase-3-dependent apoptosis in U-87 MG cells.…”

Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in Medulloblastoma Cells: Involvement of HDACs and EGFR

“…RA inhibits EGF-induced EGFR activation, leading to downregulation of PI3K/AKT and MAPK/ERK and reduction in the viability and migration of head and neck squamous cell carcinoma cell lines (Tumur et al 2015). Also, computational and theoretical data suggest RA binds directly to EGFR, acting as a pharmacological inhibitor of the receptor (Balogun et al, 2021).…”

“…Studies have previously demonstrated that RA can modulate HDAC expression (Ferdousi et al 2019;Jang et al 2018) and EGFR activity (Balogun et al 2021;Tumur et al 2015), which are targets for MB therapies. Although its antitumor effects against other types of central nervous system (CNS) cancer cell lines have been demonstrated (Khan et al 2019;Ramanauskiene et al 2016;Şengelen and Önay-Uçar 2018), previous studies have not examined its possible effects in MB models.…”

Effect of rosmarinic acid as a chemopreventive modality on experimentally induced hamster buccal pouch carcinogenesis

“…Diterpenes carnosic acid and rosmarinic acid (RA) are the main polyphenols found in rosemary extract (18) . RA have a therapeutic role, with respect to its anti-oxidant, and anti-inflammatory activities (20) . Pervious literature had described the growth inhibitory and anti-invasion properties of RA in colon, skin, breast and ovarian cancers in vitro and/or in vivo but the mechanisms underlying these effects are poorly understood (21)(22)(23)(24) .…”