Inhibition of chloride intracellular channel 1 (CLIC1) as biguanide class-effect to impair human glioblastoma stem cell viability

Federica Barbieri, Roberto Würth, Alessandra Pattarozzi, Ivan Verduci, Chiara Mazzola, Maria G. Cattaneo, Michele Tonelli, Agnese Solari, Adriana Bajetto, Antonio Daga, Lucia M. Vicentini, Michele Mazzanti, Tullio Florio

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50 values significantly lower than metformin, (range 0.054-0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanidestructured molecules, characterized by high antitumor efficacy and safe toxicological profile.

Original languageEnglish
Article number899
JournalFrontiers in Pharmacology
Volume9
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Biguanides
Metformin
Glioblastoma
Cell Survival
Stem Cells
Proguanil
Phenformin
Mesenchymal Stromal Cells
Hypoglycemic Agents
Pharmaceutical Preparations
Cell Proliferation
rat CLIC1 protein
Umbilical Cord
Antimalarials
Toxicology
Inhibitory Concentration 50
Antiviral Agents
Neoplasms
Ions

Keywords

  • Biguanides
  • Cancer stem cells
  • CLIC1
  • Glioblastoma
  • Metformin
  • Proliferation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Inhibition of chloride intracellular channel 1 (CLIC1) as biguanide class-effect to impair human glioblastoma stem cell viability. / Barbieri, Federica; Würth, Roberto; Pattarozzi, Alessandra; Verduci, Ivan; Mazzola, Chiara; Cattaneo, Maria G.; Tonelli, Michele; Solari, Agnese; Bajetto, Adriana; Daga, Antonio; Vicentini, Lucia M.; Mazzanti, Michele; Florio, Tullio.

In: Frontiers in Pharmacology, Vol. 9, 899, 01.01.2018.

Research output: Contribution to journalArticle

Barbieri, F, Würth, R, Pattarozzi, A, Verduci, I, Mazzola, C, Cattaneo, MG, Tonelli, M, Solari, A, Bajetto, A, Daga, A, Vicentini, LM, Mazzanti, M & Florio, T 2018, 'Inhibition of chloride intracellular channel 1 (CLIC1) as biguanide class-effect to impair human glioblastoma stem cell viability', Frontiers in Pharmacology, vol. 9, 899. https://doi.org/10.3389/fphar.2018.00899
Barbieri, Federica ; Würth, Roberto ; Pattarozzi, Alessandra ; Verduci, Ivan ; Mazzola, Chiara ; Cattaneo, Maria G. ; Tonelli, Michele ; Solari, Agnese ; Bajetto, Adriana ; Daga, Antonio ; Vicentini, Lucia M. ; Mazzanti, Michele ; Florio, Tullio. / Inhibition of chloride intracellular channel 1 (CLIC1) as biguanide class-effect to impair human glioblastoma stem cell viability. In: Frontiers in Pharmacology. 2018 ; Vol. 9.
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AU - Mazzola, Chiara

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AU - Tonelli, Michele

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N2 - The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50 values significantly lower than metformin, (range 0.054-0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanidestructured molecules, characterized by high antitumor efficacy and safe toxicological profile.

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