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Combinatorial Therapeutic Effect of Inhibitors of Aldehyde Dehydrogenase and Mitochondrial Complex I, and the Chemotherapeutic Drug, Temozolomide against Glioblastoma Tumorspheres

 Hun Ho Park  ;  Junseong Park  ;  Hye Joung Cho  ;  Jin-Kyoung Shim  ;  Ju Hyung Moon  ;  Eui Hyun Kim  ;  Jong Hee Chang  ;  Soo Youl Kim  ;  Seok-Gu Kang 
 MOLECULES, Vol.26(2) : 282, 2021-01 
Journal Title
Issue Date
Aldehyde Dehydrogenase / antagonists & inhibitors* ; Aldehyde Dehydrogenase / metabolism ; Antineoplastic Combined Chemotherapy Protocols / pharmacology* ; Brain Neoplasms* / drug therapy ; Brain Neoplasms* / enzymology ; Electron Transport Complex I / antagonists & inhibitors* ; Electron Transport Complex I / metabolism ; Enzyme Inhibitors / pharmacology ; Glioblastoma* / drug therapy ; Glioblastoma* / enzymology ; Humans ; Neoplasm Proteins / antagonists & inhibitors* ; Neoplasm Proteins / metabolism ; Spheroids, Cellular / enzymology* ; Temozolomide / pharmacology
aldehyde dehydrogenase ; bioenergenetics ; glioblastoma ; oxidative phosphorylation ; temozolomide ; tumorsphere
Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action.
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1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 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
Moon, Ju Hyung(문주형)
Park, Hun Ho(박현호) ORCID logo https://orcid.org/0000-0002-2526-9693
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
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