Investigation of Ca signaling induced by the flavonoid diosmin in glioblastoma cells and its potential implications in the treatment using the Ca chelating agent BAPTA-AM.

Flavonoids, found in fruits and vegetables, can potentially prevent brain diseases. Diosmin (diosmetin-7-O-rutinoside), a flavonoid, exhibits various pharmacological activities, but its impact on calcium ion (Ca) signaling and the associated mechanisms in human glioblastoma cells remain unclear. This study investigated the effect of diosmin on intracellular Ca levels ([Ca]), cell viability, and the participation of Ca-related pathways in DBTRG-05MG human glioblastoma cells. It also investigated the connection between Ca signaling and toxicity in cells treated with diosmin and the Ca chelator BAPTA-AM. Research indicates that diosmin (20-60 μM) caused an increase in [Ca] and induced cytotoxicity in a concentration-dependent manner. Furthermore, pre-treating the cells with the BAPTA-AM can intensify the cytotoxic effect. The removal of extracellular Ca suppressed the entry of Ca. Agents that modulate store-operated Ca channels, SKF96365 and 2-APB, can inhibit the entry of Ca induced by diosmin. Treatment with the endoplasmic reticulum Ca pump inhibitor thapsigargin in a Ca-free environment inhibited the increase in [Ca] caused by diosmin; conversely, treatment with diosmin reduced the increase in [Ca] caused by thapsigargin. Moreover, inhibiting phospholipase C (PLC) with U73122 eliminated the increase in [Ca] triggered by diosmin. In DBTRG-05MG cells, diosmin-induced cell death is associated with Ca, a process involving the entry of Ca through store-operated Ca channels and the release of Ca from the endoplasmic reticulum, which relies on the PLC. Additionally, BAPTA-AM, a compound with Ca-chelating properties, shows promise in enhancing diosmin-induced cytotoxicity, and this could represent a significant development in glioblastoma research.