PMID- 17289897
OWN - NLM
STAT- MEDLINE
DCOM- 20070504
LR  - 20071203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 13
IP  - 3
DP  - 2007 Feb 1
TI  - Cell type-specific, topoisomerase II-dependent inhibition of hypoxia-inducible 
      factor-1alpha protein accumulation by NSC 644221.
PG  - 1010-8
AB  - PURPOSE: The discovery and development of small-molecule inhibitors of 
      hypoxia-inducible factor-1 (HIF-1) is an attractive, yet challenging, strategy 
      for the development of new cancer therapeutic agents. Here, we report on a novel 
      tricyclic carboxamide inhibitor of HIF-1alpha, NSC 644221. EXPERIMENTAL DESIGN: 
      We investigated the mechanism by which the novel compound NSC 644221 inhibited 
      HIF-1alpha. RESULTS: NSC 644221 inhibited HIF-1-dependent, but not constitutive, 
      luciferase expression in U251-HRE and U251-pGL3 cells, respectively, as well as 
      hypoxic induction of vascular endothelial growth factor mRNA expression in U251 
      cells. HIF-1alpha, but not HIF-1beta, protein expression was inhibited by NSC 
      644221 in a time- and dose-dependent fashion. Interestingly, NSC 644221 was 
      unable to inhibit HIF-1alpha protein accumulation in the presence of the 
      proteasome inhibitors MG132 or PS341, yet it did not directly affect the 
      degradation of HIF-1alpha as shown by experiments done in the presence of 
      cyclohexamide or pulse-chase labeling using [35S]methionine. In contrast, NSC 
      644221 decreased the rate of HIF-1alpha translation relative to untreated 
      controls. Silencing of topoisomerase (topo) IIalpha, but not topo I, by specific 
      small interfering RNA completely blocked the ability of NSC 644221 to inhibit 
      HIF-1alpha. The data presented show that topo II is required for the inhibition 
      of HIF-1alpha by NSC 644221. Furthermore, although NSC 644221 induced p21 
      expression, gammaH2A.X, and G2-M arrest in the majority of cell lines tested, it 
      only inhibited HIF-1alpha in a distinct subset of cells, raising the possibility 
      of pathway-specific "resistance" to HIF-1 inhibition in cancer cells. 
      CONCLUSIONS: NSC 644221 is a novel HIF-1 inhibitor with potential for use as both 
      an analytic tool and a therapeutic agent. Our data provide a strong rationale for 
      pursuing the preclinical development of NSC 644221 as a HIF-1 inhibitor.
FAU - Creighton-Gutteridge, Mark
AU  - Creighton-Gutteridge M
AD  - Screening Technologies Branch, Developmental Therapeutics Program, 
      SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 
      21702, USA.
FAU - Cardellina, John H 2nd
AU  - Cardellina JH 2nd
FAU - Stephen, Andrew G
AU  - Stephen AG
FAU - Rapisarda, Annamaria
AU  - Rapisarda A
FAU - Uranchimeg, Badarch
AU  - Uranchimeg B
FAU - Hite, Karen
AU  - Hite K
FAU - Denny, William A
AU  - Denny WA
FAU - Shoemaker, Robert H
AU  - Shoemaker RH
FAU - Melillo, Giovanni
AU  - Melillo G
LA  - eng
GR  - N01-CO-12400/CO/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
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 (Amides)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NSC 644221)
RN  - 0 (Polycyclic Compounds)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 5.99.1.3 (DNA Topoisomerases, Type II)
SB  - IM
MH  - Amides/*pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - DNA Topoisomerases, Type II/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors
MH  - Luciferases/metabolism
MH  - Models, Chemical
MH  - Neoplasms/*drug therapy
MH  - Polycyclic Compounds/*pharmacology
MH  - RNA, Messenger/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Temperature
MH  - Time Factors
MH  - Transfection
EDAT- 2007/02/10 09:00
MHDA- 2007/05/05 09:00
CRDT- 2007/02/10 09:00
PHST- 2007/02/10 09:00 [pubmed]
PHST- 2007/05/05 09:00 [medline]
PHST- 2007/02/10 09:00 [entrez]
AID - 13/3/1010 [pii]
AID - 10.1158/1078-0432.CCR-06-2301 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2007 Feb 1;13(3):1010-8. doi: 10.1158/1078-0432.CCR-06-2301.