METFORMIN, CLIC1 AND TRANSCRANIAL STIMULATION: THE BASIS OF A NEW TARGETED THERAPY AGAINST GLIOBLASTOMA RELAPSE
type: CreativeWork
description: Glioblastoma (GBM) is the most prevalent type of brain tumor and has a very poor prognosis. The current standard of care includes surgery to remove the mass of the tumor, followed by chemoradiation therapy. However, this technique is neither effective nor specific, and tumor recurrence occurs frequently, often fatally. As a result, new techniques for preventing glioblastoma relapse and increasing patients' life expectancy should be developed. GBM stem-like cells (GSCs) are primarily responsible for the high level of aggressiveness and recurrence. GSCs drive tumorigenesis and self-renewal, confer resistance to the tumor and guide tumor relapse. Recent publications proposed the transmembrane CLIC1 protein (tmCLIC1) as a potential pharmacological target since it is crucial for GSCs proliferation. tmCLIC1 inhibition shows tumor growth impairment both in vitro and in vivo. Recently, tmCLIC1 has been proposed to be one of metformin’s targets. In this work, we show molecular and functional evidence of the direct metformin-CLIC1 interaction, by NMR, MicroScale Thermophoresis, and single-channel patch-clamp experiments. However, due to the blood brain barrier, the high concentration of metformin (10mM) required to inhibit tumor progression, which has been beneficial in other types of tumors, cannot be reached in the brain. As a result, the primary goal of this study is to improve metformin antitumoral activity on glioblastoma by lowering its operative concentration to a level that allows it to enter the brain. Our strategy is to induce repetitive membrane depolarizations to the tumor to promote metformin-tmCLIC1 binding. In fact, interaction between the two only occurs when tmCLIC1 is in the open state. Pulsed depolarizing electromagnetic field (EMF) stimulation should increase tmCLIC1 close-to-open transitions and, consequently, the availability of metformin binding sites. The application of EMF stimulation resulted in a 10-fold decrease of metformin concentration (1mM) nee…
abstract: Glioblastoma (GBM) is the most prevalent type of brain tumor and has a very poor prognosis. The current standard of care includes surgery to remove the mass of the tumor, followed by chemoradiation therapy. However, this technique is neither effective nor specific, and tumor recurrence occurs frequently, often fatally. As a result, new techniques for preventing glioblastoma relapse and increasing patients' life expectancy should be developed. GBM stem-like cells (GSCs) are primarily responsible for the high level of aggressiveness and recurrence. GSCs drive tumorigenesis and self-renewal, confer resistance to the tumor and guide tumor relapse. Recent publications proposed the transmembrane CLIC1 protein (tmCLIC1) as a potential pharmacological target since it is crucial for GSCs proliferation. tmCLIC1 inhibition shows tumor growth impairment both in vitro and in vivo. Recently, tmCLIC1 has been proposed to be one of metformin’s targets. In this work, we show molecular and functional evidence of the direct metformin-CLIC1 interaction, by NMR, MicroScale Thermophoresis, and single-channel patch-clamp experiments. However, due to the blood brain barrier, the high concentration of metformin (10mM) required to inhibit tumor progression, which has been beneficial in other types of tumors, cannot be reached in the brain. As a result, the primary goal of this study is to improve metformin antitumoral activity on glioblastoma by lowering its operative concentration to a level that allows it to enter the brain. Our strategy is to induce repetitive membrane depolarizations to the tumor to promote metformin-tmCLIC1 binding. In fact, interaction between the two only occurs when tmCLIC1 is in the open state. Pulsed depolarizing electromagnetic field (EMF) stimulation should increase tmCLIC1 close-to-open transitions and, consequently, the availability of metformin binding sites. The application of EMF stimulation resulted in a 10-fold decrease of metformin concentration (1mM) nee…
author: CANNAVALE, GAETANO
language: eng
keywords: glioblastoma, metformin, CLIC1, Electromagnetic Field, transcranial stimulation, glioblastoma stem cell, Settore BIO/11 - Biologia Molecolare
date published: 2023-03-16
date modified: 2026-07-27T20:19:12Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/957476

PropertyValue
property ID: DOI
value: 10.13130/cannavale-gaetano_phd2023-03-16