PMID- 29971532
OWN - NLM
STAT- MEDLINE
DCOM- 20180806
LR  - 20181114
IS  - 1432-1335 (Electronic)
IS  - 0171-5216 (Linking)
VI  - 144
IP  - 9
DP  - 2018 Sep
TI  - Cell growth potential drives ferroptosis susceptibility in rhabdomyosarcoma and 
      myoblast cell lines.
PG  - 1717-1730
LID - 10.1007/s00432-018-2699-0 [doi]
AB  - PURPOSE: Ferroptosis is a programmed form of iron-dependent cell death caused by 
      lipid hydroperoxide accumulation, which can be prevented by glutathione 
      peroxidase 4 (GPx4) activity. Here we investigated the effects of ferroptosis 
      inducers called erastin and RSL3, which act by glutathione depletion and GPx4 
      inactivation, respectively, on muscle-derived cell lines of embryonal and 
      alveolar rhabdomyosarcoma (RMS), and mouse normal skeletal C2C12 myoblasts. 
      METHODS: Myogenic lines were exposed to stepwise increasing concentrations of 
      ferroptosis inducers either alone or in combination with iron supplementation, 
      iron chelating agents (bathophenanthrolinedisulfonic acid, BPS), antioxidant 
      molecules (glutathione, N-acetylcysteine), lipid peroxidation inhibitors 
      (ferrostatin-1), and chemotherapeutic agents (doxorubicin and actinomycin D). 
      Drug susceptibility was quantified by measuring cell viability, proliferation and 
      differentiation via neutral red assay, crystal violet assay and Giemsa staining, 
      respectively. The detection of lipid hydroperoxide and protein levels was 
      performed by immunofluorescence and Western blot analysis, respectively. RESULTS: 
      Erastin and RSL3 increased lipid hydroperoxide levels preferentially in the 
      embryonal U57810 and myoblast C2C12 lines, leading to ferroptosis that was 
      accentuated by iron supplementation or prevented by co-treatment with BPS, 
      glutathione, N-acetylcysteine and ferrostatin-1. The inhibition of extracellular 
      regulated kinases (ERK) pathway prevented ferroptosis in U57810 and C2C12 cells, 
      whereas its increased activation in the embryonal RD cells mediated by caveolin-1 
      (Cav-1) overexpression led to augmented ferroptosis susceptibility. Finally, we 
      observed the combination of erastin or RSL3 with chemotherapeutic doxorubicin and 
      actinomycin D agents to be effective in increasing cell death in all RMS lines. 
      CONCLUSIONS: Erastin and RSL3 trigger ferroptosis in highly 
      proliferating myogenic lines through a ERK pathway-dependent fashion.
FAU - Codenotti, Silvia
AU  - Codenotti S
AD  - Division of Biotechnology, Department of Molecular and Translational Medicine, 
      University of Brescia, Brescia, Italy.
FAU - Poli, Maura
AU  - Poli M
AD  - Division of Biotechnology, Department of Molecular and Translational Medicine, 
      University of Brescia, Brescia, Italy.
FAU - Asperti, Michela
AU  - Asperti M
AD  - Division of Biotechnology, Department of Molecular and Translational Medicine, 
      University of Brescia, Brescia, Italy.
FAU - Zizioli, Daniela
AU  - Zizioli D
AD  - Division of Biotechnology, Department of Molecular and Translational Medicine, 
      University of Brescia, Brescia, Italy.
FAU - Marampon, Francesco
AU  - Marampon F
AD  - Division of Radiation Oncology, Department of Biotechnological and Applied 
      Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
FAU - Fanzani, Alessandro
AU  - Fanzani A
AUID- ORCID: 0000-0001-7475-2668
AD  - Division of Biotechnology, Department of Molecular and Translational Medicine, 
      University of Brescia, Brescia, Italy. alessandro.fanzani@unibs.it.
LA  - eng
PT  - Journal Article
DEP - 20180703
PL  - Germany
TA  - J Cancer Res Clin Oncol
JT  - Journal of cancer research and clinical oncology
JID - 7902060
RN  - 0 (Carbolines)
RN  - 0 (Cyclohexylamines)
RN  - 0 (Phenylenediamines)
RN  - 0 (Piperazines)
RN  - 0 (RSL3 compound)
RN  - 0 (erastin)
RN  - 0 (ferrostatin-1)
RN  - 1CC1JFE158 (Dactinomycin)
RN  - 80168379AG (Doxorubicin)
RN  - EC 1.11.1.9 (Glutathione Peroxidase)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Carbolines/pharmacology
MH  - Cell Death/drug effects/*physiology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects/*physiology
MH  - Cyclohexylamines/pharmacology
MH  - Dactinomycin/pharmacology
MH  - Doxorubicin/pharmacology
MH  - Glutathione/metabolism
MH  - Glutathione Peroxidase/metabolism
MH  - Humans
MH  - Lipid Peroxidation/drug effects/physiology
MH  - Mice
MH  - Myoblasts/drug effects/metabolism/*pathology
MH  - Phenylenediamines/pharmacology
MH  - Piperazines/pharmacology
MH  - Rhabdomyosarcoma/drug therapy/metabolism/*pathology
OTO - NOTNLM
OT  - Erastin
OT  - Ferroptosis
OT  - GPx4
OT  - Iron
OT  - RSL3
OT  - Rhabdomyosarcoma
EDAT- 2018/07/05 06:00
MHDA- 2018/08/07 06:00
CRDT- 2018/07/05 06:00
PHST- 2018/05/18 00:00 [received]
PHST- 2018/06/29 00:00 [accepted]
PHST- 2018/07/05 06:00 [pubmed]
PHST- 2018/08/07 06:00 [medline]
PHST- 2018/07/05 06:00 [entrez]
AID - 10.1007/s00432-018-2699-0 [pii]
AID - 10.1007/s00432-018-2699-0 [doi]
PST - ppublish
SO  - J Cancer Res Clin Oncol. 2018 Sep;144(9):1717-1730. doi: 
      10.1007/s00432-018-2699-0. Epub 2018 Jul 3.