Purpose: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). Methods: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC–MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. Results: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC–MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. Conclusion: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.
Bibliographical noteFunding Information:
Funding was provided by National Research Foundation of Korea (Grant no. NRF-2022R1A2B5B03001199, NRF-2020M2D9A2092372, NRF-2020M3E5E2037960, NRF-2022M3C1A3096459), Yonsei University College of Medicine (Grant no. 6-2022-0147), Yonsei University (Grant no. 6-2021-0217).
This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2022R1A2B5B03001199) and the Ministry of Science and ICT (NRF-2020M2D9A2092372), the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science & ICT (NRF-2020M3E5E2037960), the “Team Science Award” of Yonsei University College of Medicine (6-2022-0147), the Hanim Precision Medicine Center of Yonsei University Health System under Grant number (6-2021-0217), and the Pioneer Research Center Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2022M3C1A3096459) to S.G.K.
© 2022, 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