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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 
 CANCER CELL INTERNATIONAL, Vol.22(1) : 309, 2022-10 
Journal Title
Issue Date
Etomoxir ; Fatty acid oxidation ; Glioblastoma ; Temozolomide ; Tumorsphere
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.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Eui Hyun(김의현) ORCID logo https://orcid.org/0000-0002-2523-7122
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Moon, Ju Hyung(문주형)
Park, Junseong(박준성)
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Yoon, Seon Jin(윤선진) ORCID logo https://orcid.org/0000-0002-3255-5081
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
Cho, Hyejoung(조혜중)
Choi, Ran Joo(최란주)
Choi, Seonah(최선아)
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