Purpose: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs). Methods: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model. Results: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test). Conclusion: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.
|Number of pages||13|
|Journal||Journal of Neuro-Oncology|
|Publication status||Published - 2022 Jan|
Bibliographical noteFunding Information:
We thank Prof. Lang (Department of Neurosurgery, M. D. Anderson Cancer Center, The University of Texas, Houston, Texas, USA) for providing patient derived GBM tumorspheres (GSC11). IM1761065 was provided by ImmunoMet Therapeutics (Houston, Texas, USA).
This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIT) (NRF-2019R1A2C3004155) and the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science & ICT (NRF-2020M3E5E2037960, NRF-2020M2D9A2092372, NRF-2020M3A9E8024890). This study was supported by the “Team Science Award” of Yonsei University College of Medicine (6-2021-0006).
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
All Science Journal Classification (ASJC) codes
- Clinical Neurology
- Cancer Research