Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres

Jin Kyoung Shim, Seonah Choi, Seon Jin Yoon, Ran Joo Choi, Junseong Park, Eun Hee Lee, Hye Joung Cho, Suji Lee, Wan Yee Teo, Ju Hyung Moon, Hyun Sil Kim, Eui Hyun Kim, Jae Ho Cheong, Jong Hee Chang, Jong In Yook, Seok Gu Kang

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Abstract

Introduction: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. Methods: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. Results: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. Conclusion: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

Original languageEnglish
Article number309
JournalCancer Cell International
Volume22
Issue number1
DOIs
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
This study was supported by grants from the National Research Foundation (NRF) of Korea funded by the Korean government (MSIT) (NRF-2022R1A2B5B03001199); the Ministry of Science and ICT (NRF-2020M2D9A2092372); the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (NRF-2020M3E5E2037960); the “Team Science Award” of Yonsei University College of Medicine (6-2021-0192); and the Hanim Precision Medicine Center of Yonsei University Health System under Grant number (6-2021-0127) to SGK.

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Genetics
  • Cancer Research

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