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© 2013. This work is published under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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 MDAMB‐468. This effect is associated with selective inhibition of translation accompanied by rapid phosphorylation of the nutrient sensing eukaryotic translation initiation factor 2α (eIF2α) 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+/Ca2+ 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 TNFα 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 eIF2α and degradation of TNFR1. These data suggest that OXY induces a multifaceted cell starvation response, which ultimately induces programmed cell death.

Details

Title
Oxyphenisatin acetate ( NSC 59687) triggers a cell starvation response leading to autophagy, mitochondrial dysfunction, and autocrine TNF α‐mediated apoptosis
Author
Morrison, Bethanie L 1 ; Mullendore, Michael E 1 ; Stockwin, Luke H 1 ; Borgel, Suzanne 2 ; Hollingshead, Melinda G 3 ; Newton, Dianne L 1 

 Drug Mechanism Group, Biological Testing Branch, Developmental Therapeutics Program, SAIC‐Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 
 In Vivo Preclinical Support Group, Biological Testing Branch, Developmental Therapeutics Program, SAIC‐Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 
 Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, Frederick, Maryland 
Pages
687-700
Section
Clinical Cancer Research
Publication year
2013
Publication date
Oct 2013
Publisher
John Wiley & Sons, Inc.
e-ISSN
20457634
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2290088342
Copyright
© 2013. This work is published under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.