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JCI-20679 suppresses autophagy and enhances temozolomide-mediated growth inhibition of glioblastoma cells
Ist Teil von
Biochemical and biophysical research communications, 2022-02, Vol.591, p.62-67
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2022
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Glioblastoma, a type of brain cancer, is one of the most aggressive and lethal types of malignancy. The present study shows that JCI-20679, an originally synthesized mitochondrial complex I inhibitor, enhances the anti-proliferative effects of suboptimal concentrations of the clinically used chemotherapeutic drug temozolomide in glioblastoma cells. Analysis of the effects of temozolomide combined with JCI-20679 using isobologram and combination index methods demonstrated that the combination had synergistic effects in murine and human glioblastoma cells. We found that JCI-20679 inhibited the temozolomide-mediated induction of autophagy that facilitates cellular survival. The autophagy induced by temozolomide increased ATP production, which confers temozolomide resistance in glioblastoma cells. JCI-20679 blocked temozolomide-mediated increases in ATP levels and increased the AMP/ATP ratio. Furthermore, JCI-20679 enhanced the therapeutic effects of temozolomide in an orthotopic transplantation model of glioblastoma. These results indicate that JCI-20679 may be promising as a novel agent for enhancing the efficacy of temozolomide against glioblastoma.
•JCI-20679 synergistically enhances the effects of temozolomide on glioblastoma cells.•JCI-20679 blocks temozolomide-induced autophagy and increases in ATP levels.•JCI-20679 sensitizes an orthotropic glioblastoma mouse model to the effects of temozolomide.