PMID- 30602451
OWN - NLM
STAT- MEDLINE
DCOM- 20190722
LR  - 20200309
IS  - 1573-4935 (Electronic)
IS  - 0144-8463 (Print)
IS  - 0144-8463 (Linking)
VI  - 39
IP  - 1
DP  - 2019 Jan 31
TI  - Minerval (2-hydroxyoleic acid) causes cancer cell selective toxicity by 
      uncoupling oxidative phosphorylation and compromising bioenergetic compensation 
      capacity.
LID - BSR20181661 [pii]
LID - 10.1042/BSR20181661 [doi]
AB  - This work tests bioenergetic and cell-biological implications of the synthetic 
      fatty acid Minerval (2-hydroxyoleic acid), previously demonstrated to act by 
      activation of sphingomyelin synthase in the plasma membrane (PM) and lowering of 
      phosphatidylethanolamine (PE) and phosphatidylcholine (PC) and their carcinogenic 
      signaling. We show here that Minerval also acts, selectively in cancer cell 
      lines, as an ATP depleting uncoupler of mitochondrial oxidative phosphorylation 
      (OxPhos). As a function of its exposure time, Minerval compromised the capacity 
      of glioblastoma U87-MG cells to compensate for aberrant respiration by 
      up-modulation of glycolysis. This effect was not exposure time-dependent in the 
      lung carcinoma A549 cell line, which was more sensitive to Minerval. Compared 
      with OxPhos inhibitors FCCP (uncoupler), rotenone (electron transfer inhibitor), 
      and oligomycin (F1F0-ATPase inhibitor), Minerval action was similar only to that 
      of FCCP. This similarity was manifested by mitochondrial membrane potential (MMP) 
      depolarization, facilitation of oxygen consumption rate (OCR), restriction of 
      mitochondrial and cellular reactive oxygen species (ROS) generation and 
      mitochondrial fragmentation. Additionally, compared with other OxPhos inhibitors, 
      Minerval uniquely induced ER stress in cancer cell lines. These new modes of 
      action for Minerval, capitalizing on the high fatty acid requirements of cancer 
      cells, can potentially enhance its cancer-selective toxicity and improve its 
      therapeutic capacity.
CI  - (c) 2019 The Author(s).
FAU - Massalha, Wessal
AU  - Massalha W
AD  - Department of Neurology, Hadassah-Hebrew University Medical Center, Ein Kerem, 
      91120 Jerusalem, Israel.
FAU - Markovits, Mark
AU  - Markovits M
AD  - Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department 
      of Cell Research and Immunology, The George S. Wise Faculty for Life Sciences, 
      Sagol School of Neurosciences, Tel Aviv University, Ramat Aviv, 69978 Tel Aviv, 
      Israel.
FAU - Pichinuk, Edward
AU  - Pichinuk E
AD  - Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department 
      of Cell Research and Immunology, The George S. Wise Faculty for Life Sciences, 
      Sagol School of Neurosciences, Tel Aviv University, Ramat Aviv, 69978 Tel Aviv, 
      Israel.
FAU - Feinstein-Rotkopf, Yael
AU  - Feinstein-Rotkopf Y
AD  - Light Microscopy Lab, Core Research Facility, Faculty of Medicine, The Hebrew 
      University of Jerusalem, Ein Kerem, 91120 Jerusalem, Israel.
FAU - Tarshish, Mark
AU  - Tarshish M
AD  - Light Microscopy Lab, Core Research Facility, Faculty of Medicine, The Hebrew 
      University of Jerusalem, Ein Kerem, 91120 Jerusalem, Israel.
FAU - Mishra, Kumudesh
AU  - Mishra K
AD  - Department of Neurology, Hadassah-Hebrew University Medical Center, Ein Kerem, 
      91120 Jerusalem, Israel.
FAU - Llado, Victoria
AU  - Llado V
AD  - Laboratory of Molecular Cell Biomedicine, Department of Biology, University of 
      the Balearic Islands, Ctra. de Valldemossa km 7.5, E-07122 Palma de Mallorca, 
      Spain.
FAU - Weil, Miguel
AU  - Weil M
AD  - Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department 
      of Cell Research and Immunology, The George S. Wise Faculty for Life Sciences, 
      Sagol School of Neurosciences, Tel Aviv University, Ramat Aviv, 69978 Tel Aviv, 
      Israel.
FAU - Escriba, Pablo V
AU  - Escriba PV
AD  - Laboratory of Molecular Cell Biomedicine, Department of Biology, University of 
      the Balearic Islands, Ctra. de Valldemossa km 7.5, E-07122 Palma de Mallorca, 
      Spain.
FAU - Kakhlon, Or
AU  - Kakhlon O
AUID- ORCID: 0000-0001-7435-6454
AD  - Department of Neurology, Hadassah-Hebrew University Medical Center, Ein Kerem, 
      91120 Jerusalem, Israel ork@hadassah.org.il.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190118
PL  - England
TA  - Biosci Rep
JT  - Bioscience reports
JID - 8102797
RN  - 0 (2-hydroxy-9-cis-octadecenoic acid)
RN  - 0 (2-hydroxyoleic acid)
RN  - 0 (Oleic Acids)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
MH  - A549 Cells
MH  - Adenosine Triphosphate/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Respiration/drug effects
MH  - Electron Transport/drug effects
MH  - Energy Metabolism/*drug effects
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/metabolism/pathology
MH  - Mitochondria/drug effects/pathology
MH  - Oleic Acids/*pharmacology
MH  - Oxidative Phosphorylation/drug effects
MH  - Oxygen Consumption/drug effects
MH  - Signal Transduction/drug effects
PMC - PMC6340956
OTO - NOTNLM
OT  - Minerval (2-hydroxyoleic acid)
OT  - cancer
OT  - glycolysis
OT  - membrane lipid therapy
OT  - mitochondria
OT  - oxidative phosphorylation
COIS- The authors declare that there are no competing interests associated with the 
      manuscript.
EDAT- 2019/01/04 06:00
MHDA- 2019/07/23 06:00
PMCR- 2019/01/18
CRDT- 2019/01/04 06:00
PHST- 2018/09/15 00:00 [received]
PHST- 2018/11/27 00:00 [revised]
PHST- 2018/12/07 00:00 [accepted]
PHST- 2019/01/04 06:00 [pubmed]
PHST- 2019/07/23 06:00 [medline]
PHST- 2019/01/04 06:00 [entrez]
PHST- 2019/01/18 00:00 [pmc-release]
AID - BSR20181661 [pii]
AID - 10.1042/BSR20181661 [doi]
PST - epublish
SO  - Biosci Rep. 2019 Jan 18;39(1):BSR20181661. doi: 10.1042/BSR20181661. Print 2019 
      Jan 31.