Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current

Abstract

Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown.Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity.The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment.

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

“…Metformin induced apoptosis in the T98G cell line in a concentration-dependent manner (Ucbek et al 2014). Gritti et al (2014) demonstrated that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin blocked proliferation in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human GBMs (Gritti et al 2014).…”

“…Gritti et al (2014) demonstrated that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin blocked proliferation in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human GBMs (Gritti et al 2014). These actions accompanied to metformin-inhibition of a chloride current which is dependent on functional activity of CLIC1 (Gritti et al 2014).…”

Metformin as target metabolic drug in oncology

“…Ионный канал CLIC1 пре-имущественно активен в течение G1-S-фазы клеточного цикла [6]. Хлорные каналы (CLIC) могут быть активирова-ны внеклеточными лигандами, внутриклеточными ионами Са, цАМФ, G-белками, механическим растяжением и по-тенциалом.…”

“…Также описано, что при-менение метформина снижает заболеваемость раком поджелудочной железы [5]. Примечательно, что авторы указывают на прямую противоопухолевую активность метформина [6], мишенью для которого являются внутри-клеточные хлорные каналы в клетках глиобластомы.…”

Advances in β cell replacement and regeneration strategies for treating diabetes

“…The analysis not only confirmed regulation of targets previously shown to be controlled at the mRNA level (77,(82)(83)(84), but also identified proteins not previously associated with pregnancy-induced β cell expansion. Two examples are stathmin 1 and nuclear chloride ion channel 1, which have known roles in the regulation of cell proliferation and are being evaluated as drug targets in cancer (85)(86)(87)(88). While follow-up studies will be necessary, this study highlights the importance of global approaches to identify novel molecular targets for enhancing β cell proliferation.…”