Anti-GBM potential of Rosmarinic acid and its synthetic derivatives via targeting IL17A mediated angiogenesis pathway

Abstract

Glioblastoma (GBM) is a highly angiogenic malignant primary brain tumor with very poor patient survival rates. Here, we present Rosmarinic acid and its new salt and base derivatives that show potential anti-glioblastoma (anti-GBM) activity via disruption of IL17A-mediated downstream angiogenesis pathway. These new compounds were rationally designed, synthesized and the oral CNS physicochemical properties were determined. The anti-GBM activity of the compounds were determined using cell migration and proliferation assays in U87 MG, DBTRG MG and EA.hy926 cells. The compounds activity on IL17A and VEGF expression was determined using ELISA and apoptotic activity was measured by caspase assays. The compounds showed stability in serum and at different pH similar to Rosmarinic acid stoichiometry. Moreover, the salt derivatives were highly hydrophilic and bases were highly lipophilic. These derivatives showed blood-brain barrier permeability >2 fold more than rosmarinic acid (P<0.001). ROS were differentially expressed after treatment with salt and base rosmarinates in U87 MG (P<0.0001). The compounds showed cytostatic and anti-angiogenic activity. The IC50 of the silver salts was found to be > 1200 µg/ml thus excluding them from being classed as toxic compounds. In conclusion, metal salts and base rosmarinates demonstrated potent anti-GBM efficacy as IL17A inhibitor with minimal toxicity.

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

“…Previous studies on the effect of RA in brain cancer cell lines have shown different sensibility to the compound. In the glioblastoma cell line U-87 MG, the estimated IC 50 following 72 h RA-exposure was 40 μM (Khan et al 2019). Using the same cell line and a 48h RA-treatment protocol, the estimated IC 50 was 373.48 μM (Şengelen and Önay-Uçar 2018).…”

“…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.…”

The role of IL-17 in the pathogenesis and treatment of glioblastoma—an update on the state of the art and future perspectives

“…FLVM also showed an immunomodulatory effect on GBM TME. Both molecules downregulated HIF-1α, reducing hypoxia in the GBM tissue and promoting its apoptosis by increasing the levels of reactive oxygen species [ 72 , 98 ].…”