Inhibition of Radiation and Temozolomide-Induced Glioblastoma Invadopodia Activity Using Ion Channel Drugs

SIMPLE SUMMARY: Glioblastoma accounts for approximately 40–50% of all primary brain cancers and is a highly aggressive cancer that rapidly disseminates within the surrounding normal brain. Dynamic actin-rich protrusions known as invadopodia facilitate this invasive process. Ion channels have also been linked to a pro-invasive phenotype and may contribute to facilitating invadopodia activity in cancer cells. The aim of our study was to screen ion channel-targeting drugs for their cytotoxic efficacy and potential anti-invadopodia properties in glioblastoma cells. We demonstrated that the targeting of ion channels in glioblastoma cells can lead to a reduction in invadopodia activity and protease secretion. Importantly, the candidate drugs exhibited a significant reduction in radiation and temozolomide-induced glioblastoma cell invadopodia activity. These findings support the proposed pro-invasive role of ion channels via invadopodia in glioblastoma, which may be ideal therapeutic targets for the treatment of glioblastoma patients. ABSTRACT: Glioblastoma (GBM) is the most prevalent and malignant type of primary brain cancer. The rapid invasion and dissemination of tumor cells into the surrounding normal brain is a major driver of tumor recurrence, and long-term survival of GBM patients is extremely rare. Actin-rich cell membrane protrusions known as invadopodia can facilitate the highly invasive properties of GBM cells. Ion channels have been proposed to contribute to a pro-invasive phenotype in cancer cells and may also be involved in the invadopodia activity of GBM cells. GBM cell cytotoxicity screening of several ion channel drugs identified three drugs with potent cell killing efficacy: flunarizine dihydrochloride, econazole nitrate, and quinine hydrochloride dihydrate. These drugs demonstrated a reduction in GBM cell invadopodia activity and matrix metalloproteinase-2 (MMP-2) secretion. Importantly, the treatment of GBM cells with these drugs led to a significant reduction in radiation/temozolomide-induced invadopodia activity. The dual cytotoxic and anti-invasive efficacy of these agents merits further research into targeting ion channels to reduce GBM malignancy, with a potential for future clinical translation in combination with the standard therapy.