Abstract 4705: Repetitive membrane potential oscillations enhance metformin's antiproliferative effect in glioblastoma stem cells

Abstract

Abstract Glioblastoma (GB) is the most common and lethal brain tumor and there is a general agreement that GB stem cells (GSCs) are primarily responsible for its high aggressiveness and recurrence. It was recently reported that GSCs are enriched in the transmembrane form of CLIC1 protein (tmCLIC1) and its inhibition was shown to impair tumor growth both in vitro and in vivo. IAA94 hampers tmCLIC1 function but could not be used in clinics. However, tmCLIC1 is also sensitive to metformin, the most used drug to treat type-2 diabetes. Metformin has been demonstrated to have the same effect as IAA94 in in vitro experiments, resulting in an antitumoral action on cancer cells. Moreover, GB orthotopic mouse model treated with metformin shows a 50% survival compared to control animals, even if metformin concentration in the mice brain resulted in the nanomolar range. In this scenario, the main aim of this work is to enhance the effect of metformin able to reach the brain, improving its antitumoral activity in GB. The interaction between metformin and tmCLIC1 occurs only when this protein is in its open state. TmCLIC1 has the peculiarity of being a voltage-dependent ion channel that opens at depolarized voltages. Thus, our strategy is to apply electromagnetic field (EMF) stimulation to induce repetitive membrane depolarization, increasing metformin-tmCLIC1 binding. Our results show that EMF stimulation induces the close-to-open transitions of tmCLIC1, resulting in a 10-fold decrease of the operative concentration of Metformin. This was verified initially in vitro with GSC culture and spheroids model and afterward confirmed also in an in vivo model. The project’s long-term goal is to combine transcranial stimulation and metformin administration in patients as an adjuvant therapy able to target cells that are resistant to chemotherapy and drive tumor relapse. Citation Format: Ivan Verduci, Gaetano Cannavale, Guido Rey, Francesca Cianci, Alessandro Fantin, Michele Mazzanti. Repetitive membrane potential oscillations enhance metformin's antiproliferative effect in glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4705.