PMID- 29294080
OWN - NLM
STAT- MEDLINE
DCOM- 20191008
LR  - 20210103
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 20
IP  - 7
DP  - 2018 Jun 18
TI  - Regulation of bioenergetics through dual inhibition of aldehyde dehydrogenase and 
      mitochondrial complex I suppresses glioblastoma tumorspheres.
PG  - 954-965
LID - 10.1093/neuonc/nox243 [doi]
AB  - BACKGROUND: Targeted approaches for treating glioblastoma (GBM) attempted to date 
      have consistently failed, highlighting the imperative for treatment strategies 
      that operate on different mechanistic principles. Bioenergetics deprivation has 
      emerged as an effective therapeutic approach for various tumors. We have 
      previously found that cancer cells preferentially utilize cytosolic NADH supplied 
      by aldehyde dehydrogenase (ALDH) for ATP production through oxidative 
      phosphorylation (OxPhos). This study is aimed at examining therapeutic responses 
      and underlying mechanisms of dual inhibition of ALDH and OxPhos against GBM. 
      METHODS: For inhibition of ALDH and OxPhos, the corresponding inhibitors, 
      gossypol and phenformin were used. Biological functions, including ATP levels, 
      stemness, invasiveness, and viability, were evaluated in GBM tumorspheres (TSs). 
      Gene expression profiles were analyzed using microarray data. In vivo anticancer 
      efficacy was examined in a mouse orthotopic xenograft model. RESULTS: Combined 
      treatment of GBM TSs with gossypol and phenformin significantly reduced ATP 
      levels, stemness, invasiveness, and cell viability. Consistently, this therapy 
      substantially decreased expression of genes associated with stemness, mesenchymal 
      transition, and invasion in GBM TSs. Supplementation of ATP using malate 
      abrogated these effects, whereas knockdown of ALDH1L1 mimicked them, suggesting 
      that disruption of ALDH-mediated ATP production is a key mechanism of this 
      therapeutic combination. In vivo efficacy confirmed remarkable therapeutic 
      responses to combined treatment with gossypol and phenformin. CONCLUSION: Our 
      findings suggest that dual inhibition of tumor bioenergetics is a novel and 
      effective strategy for the treatment of GBM.
FAU - Park, Junseong
AU  - Park J
AD  - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei 
      University College of Medicine, Seoul, Republic of Korea.
FAU - Shim, Jin-Kyoung
AU  - Shim JK
AD  - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei 
      University College of Medicine, Seoul, Republic of Korea.
FAU - Kang, Joon Hee
AU  - Kang JH
AD  - Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer 
      Center, Goyang, Republic of Korea.
FAU - Choi, Junjeong
AU  - Choi J
AD  - College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei 
      University, Incheon, Republic of Korea.
FAU - Chang, Jong Hee
AU  - Chang JH
AD  - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei 
      University College of Medicine, Seoul, Republic of Korea.
FAU - Kim, Soo-Youl
AU  - Kim SY
AD  - Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer 
      Center, Goyang, Republic of Korea.
FAU - Kang, Seok-Gu
AU  - Kang SG
AD  - Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei 
      University College of Medicine, Seoul, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Contraceptive Agents, Male)
RN  - 0 (Hypoglycemic Agents)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - DD5K7529CE (Phenformin)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - KAV15B369O (Gossypol)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Aldehyde Dehydrogenase/*antagonists & inhibitors
MH  - Animals
MH  - Biomarkers, Tumor/genetics
MH  - Brain Neoplasms/metabolism/pathology/*prevention & control
MH  - Cell Proliferation
MH  - Contraceptive Agents, Male/pharmacology
MH  - Electron Transport Complex I/*antagonists & inhibitors
MH  - Energy Metabolism/*drug effects
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Glioblastoma/metabolism/pathology/*prevention & control
MH  - Gossypol/pharmacology
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Mitochondria/drug effects/metabolism/pathology
MH  - Neoplasm Invasiveness
MH  - Neoplastic Stem Cells/*drug effects/metabolism/pathology
MH  - Oxidative Phosphorylation/*drug effects
MH  - Phenformin/pharmacology
MH  - Prognosis
MH  - Survival Rate
MH  - Xenograft Model Antitumor Assays
PMC - PMC6007558
EDAT- 2018/01/03 06:00
MHDA- 2019/10/09 06:00
PMCR- 2019/06/18
CRDT- 2018/01/03 06:00
PHST- 2018/01/03 06:00 [pubmed]
PHST- 2019/10/09 06:00 [medline]
PHST- 2018/01/03 06:00 [entrez]
PHST- 2019/06/18 00:00 [pmc-release]
AID - 4773887 [pii]
AID - nox243 [pii]
AID - 10.1093/neuonc/nox243 [doi]
PST - ppublish
SO  - Neuro Oncol. 2018 Jun 18;20(7):954-965. doi: 10.1093/neuonc/nox243.