PMID- 16144942
OWN - NLM
STAT- MEDLINE
DCOM- 20051101
LR  - 20220317
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 11
IP  - 17
DP  - 2005 Sep 1
TI  - Transcriptional profiling identifies altered intracellular labile iron 
      homeostasis as a contributing factor to the toxicity of adaphostin: decreased 
      vascular endothelial growth factor secretion is independent of hypoxia-inducible 
      factor-1 regulation.
PG  - 6370-81
AB  - PURPOSE: Adaphostin was developed as an inhibitor of the p210(bcr-abl) tyrosine 
      kinase, but as its activity is not limited to tumor cell lines containing this 
      translocation, transcriptional profiling was used as a tool to elucidate 
      additional mechanisms responsible for adaphostin cytotoxicity. EXPERIMENTAL 
      DESIGN: Profiles of drug-induced transcriptional changes were measured in three 
      hematopoietic cell lines following 1 and 10 micromol/L adaphostin for 2 to 6 
      hours and then confirmed with real-time reverse transcription-PCR (2-24 hours). 
      These data indicated altered iron homeostasis, and this was confirmed 
      experimentally. Alteration of vascular endothelial growth factor (VEGF) secretion 
      through hypoxia-inducible factor-1 (HIF-1) regulation was also investigated. 
      RESULTS: Drug-induced genes included heat shock proteins and ubiquitins, but an 
      intriguing response was the induction of ferritins. Measurement of the labile 
      iron pool showed release of chelatable iron immediately after treatment with 
      adaphostin and was quenched with the addition of an iron chelator. Pretreatment 
      of cells with desferrioxamine and N-acetyl-cysteine reduced but did not ablate 
      the sensitivity of the cells to adaphostin, and desferrioxamine was able to 
      modulate adaphostin-induced activation of p38 and inactivation of AKT. VEGF 
      secretion was shown to be reduced in cell lines after the addition of adaphostin 
      but was not dependent on HIF-1. CONCLUSIONS: Adaphostin-induced cytotoxicity is 
      caused in part by a rapid release of free iron, leading to redox perturbations 
      and cell death. Despite this, reduced VEGF secretion was found to be independent 
      of regulation by the redox responsive transcription factor HIF-1. Thus, 
      adaphostin remains an interesting agent with the ability to kill tumor cells 
      directly and modulate angiogenesis.
FAU - Hose, Curtis
AU  - Hose C
AD  - SAIC Frederick, Inc., Screening Technologies Branch, Laboratory of Functional 
      Genomics, National Cancer Institute Frederick, Frederick, Maryland 21702, USA.
FAU - Kaur, Gurmeet
AU  - Kaur G
FAU - Sausville, Edward A
AU  - Sausville EA
FAU - Monks, Anne
AU  - Monks A
LA  - eng
GR  - N01-C0-12400/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antioxidants)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Drug Combinations)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hydroquinones)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Iron Chelating Agents)
RN  - 0 (NSC 680410)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Transferrin)
RN  - 0 (Transcription Factors)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - E1UOL152H7 (Iron)
RN  - PJY633525U (Adamantane)
SB  - IM
MH  - Adamantane/*analogs & derivatives/pharmacology
MH  - Antioxidants/pharmacology
MH  - Cell Hypoxia
MH  - Culture Media, Conditioned/pharmacology
MH  - Drug Combinations
MH  - Gene Expression Profiling
MH  - *Gene Expression Regulation, Neoplastic
MH  - HL-60 Cells
MH  - Humans
MH  - Hydroquinones/*pharmacology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Iron/*metabolism
MH  - Iron Chelating Agents/pharmacology
MH  - Jurkat Cells
MH  - K562 Cells
MH  - Molecular Structure
MH  - Oligonucleotide Array Sequence Analysis
MH  - Oxidative Stress
MH  - RNA, Messenger/genetics/metabolism
MH  - Receptors, Transferrin/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transcription Factors/*pharmacology
MH  - Transcription, Genetic/*drug effects
MH  - Vascular Endothelial Growth Factor A/*metabolism
EDAT- 2005/09/08 09:00
MHDA- 2005/11/03 09:00
CRDT- 2005/09/08 09:00
PHST- 2005/09/08 09:00 [pubmed]
PHST- 2005/11/03 09:00 [medline]
PHST- 2005/09/08 09:00 [entrez]
AID - 11/17/6370 [pii]
AID - 10.1158/1078-0432.CCR-05-0291 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2005 Sep 1;11(17):6370-81. doi: 10.1158/1078-0432.CCR-05-0291.