JCI-20679 suppresses autophagy and enhances temozolomide-mediated growth inhibition of glioblastoma cells.

Abstract

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.

• Authors: Shota Ando, Chiami Moyama, Naoto Kojima, Mitsugu Fujita, Kaito Ohta, Yukina Kohno, Hiromi Ii, Susumu Nakata
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 591 Pg. 62-67 (02 05 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 34999255 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Adenosine Triphosphate
• Temozolomide
• JCI 20679

Topics

• Animals
• Humans
• Adenosine Triphosphate (metabolism)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Glioblastoma (pathology)
• Mice, SCID
• Temozolomide (pharmacology)