Apigenin from Croton betulaster Müll restores the immune profile of microglia against glioma cells

Abstract

The flavonoid apigenin, extracted from the Brazilian plant Croton betulaster Müll. has demonstrated the ability to inhibit proliferation, induce differentiation, and modify the inflammatory profile of glioma cells. The aim of the present study was to evaluate the effect of apigenin on chemotaxis and regulation of inflammatory cytokines of microglia cells and these impacts on glioma cell growth. In cultures of isolated rat microglia, it was observed that apigenin induced changes in Iba1‐positive cells to an ameboid phenotype, associated to an increase in the expression of the activated M1 profile marker OX‐42 and iNOS and a reduction in the expression of the M2 profile marker CD206. Besides, apigenin modulated the tumor necrosis factor and IL‐10 release by microglia. Treatment of C6 glioma cells with conditioned medium of microglia treated with apigenin‐induced reduction of tumor migration and viability, associated with significant reduction in IL‐6 levels. On the other hand, treatment of C6 cells with apigenin‐induced microglia chemotaxis to glioma in vitro. Moreover, apigenin treatment of microglia/C6 co‐cultures induced preferentially reduction in the viability of C6 cells and increased microglia‐activated phenotype, associated with a change in the balance of TNF/IL‐10 levels. Together, these results demonstrated that the flavonoid apigenin restores the immune profile of microglia against glioma cells.

Neuroimmunomodulatory Properties of Flavonoids and Derivates: A Potential Action as Adjuvants for the Treatment of Glioblastoma

“…Studies conducted over the last two decades, and especially in the last years, have demonstrated the antitumor potential of the flavonoids both in in vitro and in in vivo models of GBMs [5][6][7][8]. Moreover, these compounds also showed the potential to modulate the inflammatory response of microglia/macrophages associated with tumorigenesis inhibition [9][10][11]. The present review discusses the main aspects of GBM physiopathology and advances in the interaction between tumor and microenvironment.…”

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

“…Reduced cell viability and proliferation [359][360][361]. Induced cell cycle arrest at the G1 or G2/M phase [360,362,363]. Inhibited hypoxia-induced resistance via suppression of HIF-1α [362].…”

“…When treated with conditioned medium of microglia treated with apigenin, C6 glioma cells exhibited reduced tumor migration and viability, due to the reduction in IL-6 levels. Apigenin also preferentially reduced viability of C6 glioma cells when co-cultured with microglia [363]. One study showed that apigenin inhibited cell proliferation, induced apoptosis, reduced vascular endothelial growth factor (VEGF) expression, and reduced tumor-induced angiogenesis in two human esophageal cancer models [361].…”

Neuroimmunomodulatory and Neuroprotective Effects of the Flavonoid Apigenin in in vitro Models of Neuroinflammation Associated With Alzheimer’s Disease

“…Apigenin (4,5,7-trihydroxyflavone) is a flavonoid belonging to the class of flavones, found in abundance in fruits and teas (McKay and Blumberg, 2006;Gazola et al, 2015). Studies have shown several biological activities associated with apigenin treatment, such as antioxidant (Han et al, 2012), anti-inflammatory (Lee et al, 2015), neurogenic (Souza et al, 2015), neuroprotective (Balez et al, 2016), and antitumor (Coelho et al, 2019). Importantly, apigenin can cross the bloodbrain barrier (Popović et al, 2014), which is of great significance to treat CNS disorders.…”