PMID- 24403234
OWN - NLM
STAT- MEDLINE
DCOM- 20140916
LR  - 20211203
IS  - 2045-7634 (Electronic)
IS  - 2045-7634 (Print)
IS  - 2045-7634 (Linking)
VI  - 2
IP  - 5
DP  - 2013 Oct
TI  - Oxyphenisatin acetate (NSC 59687) triggers a cell starvation response leading to 
      autophagy, mitochondrial dysfunction, and autocrine TNFalpha-mediated apoptosis.
PG  - 687-700
LID - 10.1002/cam4.107 [doi]
AB  - Oxyphenisatin (3,3-bis(4-hydroxyphenyl)-1H-indol-2-one) and several structurally 
      related molecules have been shown to have in vitro and in vivo antiproliferative 
      activity. This study aims to confirm and extend mechanistic studies by focusing 
      on oxyphenisatin acetate (OXY, NSC 59687), the pro-drug of oxyphenisatin. Results 
      confirm that OXY inhibits the growth of the breast cancer cell lines MCF7, T47D, 
      HS578T, and MDA-MB-468. This effect is associated with selective inhibition of 
      translation accompanied by rapid phosphorylation of the nutrient sensing 
      eukaryotic translation initiation factor 2alpha (eIF2alpha) kinases, GCN2 and PERK. This 
      effect was paralleled by activation of AMP-activated protein kinase (AMPK) 
      combined with reduced phosphorylation of the mammalian target of rapamycin (mTOR) 
      substrates p70S6K and 4E-BP1. Microarray analysis highlighted activation of 
      pathways involved in apoptosis induction, autophagy, RNA/protein metabolism, 
      starvation responses, and solute transport. Pathway inhibitor combination studies 
      suggested a role for AMPK/mTOR signaling, de novo transcription and translation, 
      reactive oxygen species (ROS)/glutathione metabolism, calcium homeostasis and 
      plasma membrane Na(+) /K(+) /Ca(2+) transport in activity. Further examination 
      confirmed that OXY treatment was associated with autophagy, mitochondrial 
      dysfunction, and ROS generation. Additionally, treatment was associated with 
      activation of both intrinsic and extrinsic apoptotic pathways. In the estrogen 
      receptor (ER) positive MCF7 and T47D cells, OXY induced TNFalpha expression and TNFR1 
      degradation, indicating autocrine receptor-mediated apoptosis in these lines. 
      Lastly, in an MCF7 xenograft model, OXY delivered intraperitoneally inhibited 
      tumor growth, accompanied by phosphorylation of eIF2alpha and degradation of TNFR1. 
      These data suggest that OXY induces a multifaceted cell starvation response, 
      which ultimately induces programmed cell death.
CI  - (c) 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
FAU - Morrison, Bethanie L
AU  - Morrison BL
AD  - Drug Mechanism Group, Biological Testing Branch, Developmental Therapeutics 
      Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, 
      Frederick, Maryland, 21702.
FAU - Mullendore, Michael E
AU  - Mullendore ME
FAU - Stockwin, Luke H
AU  - Stockwin LH
FAU - Borgel, Suzanne
AU  - Borgel S
FAU - Hollingshead, Melinda G
AU  - Hollingshead MG
FAU - Newton, Dianne L
AU  - Newton DL
LA  - eng
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - HHSN261200 800001E/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130723
PL  - United States
TA  - Cancer Med
JT  - Cancer medicine
JID - 101595310
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Tnfrsf1a protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.1 (Eif2ak4 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (eIF2alpha kinase, mouse)
RN  - U0Y1YAL65X (Oxyphenisatin Acetate)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Autocrine Communication/drug effects
MH  - Autophagy/*drug effects
MH  - Breast Neoplasms/metabolism/*pathology
MH  - Cell Proliferation/drug effects
MH  - Drug Evaluation, Preclinical/methods
MH  - Female
MH  - Humans
MH  - Mammary Neoplasms, Experimental/metabolism/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Mitochondria/*drug effects/physiology
MH  - Neoplasm Proteins/metabolism
MH  - Oxyphenisatin Acetate/*pharmacology
MH  - Phosphorylation/drug effects
MH  - Protein Biosynthesis/drug effects
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Receptors, Tumor Necrosis Factor, Type I/metabolism
MH  - Tissue Array Analysis/methods
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/physiology
MH  - Xenograft Model Antitumor Assays/methods
PMC - PMC3892800
OTO - NOTNLM
OT  - Autophagy
OT  - TNFalpha
OT  - breast cancer
OT  - oxyphenisatin
OT  - protein synthesis
EDAT- 2014/01/10 06:00
MHDA- 2014/09/17 06:00
PMCR- 2013/10/01
CRDT- 2014/01/10 06:00
PHST- 2013/03/28 00:00 [received]
PHST- 2013/06/11 00:00 [revised]
PHST- 2013/06/12 00:00 [accepted]
PHST- 2014/01/10 06:00 [entrez]
PHST- 2014/01/10 06:00 [pubmed]
PHST- 2014/09/17 06:00 [medline]
PHST- 2013/10/01 00:00 [pmc-release]
AID - 10.1002/cam4.107 [doi]
PST - ppublish
SO  - Cancer Med. 2013 Oct;2(5):687-700. doi: 10.1002/cam4.107. Epub 2013 Jul 23.