PMID- 27877208
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211201
IS  - 1837-9664 (Print)
IS  - 1837-9664 (Electronic)
IS  - 1837-9664 (Linking)
VI  - 7
IP  - 14
DP  - 2016
TI  - Selection, Analysis and Improvement of Anti-Angiogenesis Compounds Identified by 
      an Anti-HIF-1alpha Screening and Validation System.
PG  - 1926-1938
AB  - Cancer cells resort to activating hypoxia-inducible factor-1 (HIF-1) as one of 
      several responses to hypoxic conditions. Overexpression of HIF-1, the 
      transcriptional regulator for a group of malignant-pathway related genes 
      including vascular endothelial growth factor (VEGF), is associated with increased 
      tumor growth, vascularization, and metastasis. HIF-1 is composed of an inducible 
      subunit, HIF-1alpha and a constitutively expressed subunit, HIF-1ss. HIF-1 activity is 
      mainly dependent on the level of HIF-1alpha protein, the inducible and regulatory 
      subunit of the HIF-1 heterodimer complex; thus, identification of novel 
      anti-HIF-1alpha agents will lead to effective blockage of the HIF-1 (HIF-1alpha)-mediated 
      "switch-on" function for those malignant-pathway related genes and suppression of 
      the HIF-1alpha/VEGF-mediated signaling pathway that promotes cancer progression and 
      metastasis. While there is an extremely large number of small molecule compounds 
      in the database (compound libraries), the currently existing screening system is 
      inefficient and time-consuming; or, at best, the application of the existing 
      screening system is very limited as it is usually not coupled with biological 
      validation processes. The further development of potential drugs is partly 
      hindered due to the cumbersome steps in between the primary screen and consequent 
      validation: the slow, exhausted and sometimes lack of a linked biological 
      validation process contributes to the dismal fate of scant compounds uncovered in 
      the primary screen. To improve upon the status quo, we developed a prototype 
      screening system that is coupled anti-HIF-1alpha primary screen with secondary 
      anti-VEGF/anti-angiogenesis validation screens. We used breast cancer cells as 
      the model to select potent anti-HIF-1alpha small-molecule compounds by their 
      abilities to inhibit transactivation of a VEGF promoter fused to a luciferase 
      reporter gene under hypoxia. Positive compounds were then validated by a series 
      of assays that confirm compounds' anti-HIF-1alpha activities including measurement of 
      their effects on HIF-1alpha downstream VEGF gene expression and angiogenic ability of 
      breast cancer cells. Moreover, we demonstrated that we could further improve the 
      compound's potency of anti-HIF-1alpha and anti-angiogenesis by modifying the 
      identified lead to synthesize a superior (novel) drug.
FAU - Madu, Chikezie
AU  - Madu C
AD  - Department of Pathology and Laboratory Medicine, University of Tennessee Health 
      Science Center, Memphis, TN 38016, USA.
FAU - Li, Liyuan
AU  - Li L
AD  - Department of Pathology and Laboratory Medicine, University of Tennessee Health 
      Science Center, Memphis, TN 38016, USA.
FAU - Lu, Yi
AU  - Lu Y
AD  - Department of Pathology and Laboratory Medicine, University of Tennessee Health 
      Science Center, Memphis, TN 38016, USA.
LA  - eng
GR  - R01 CA107162/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20160927
PL  - Australia
TA  - J Cancer
JT  - Journal of Cancer
JID - 101535920
PMC - PMC5118656
OTO - NOTNLM
OT  - anti-angiogenesis
OT  - hypoxia-inducible factor-1
COIS- The authors have declared that no competing interest exists.
EDAT- 2016/11/24 06:00
MHDA- 2016/11/24 06:01
PMCR- 2016/01/01
CRDT- 2016/11/24 06:00
PHST- 2016/03/21 00:00 [received]
PHST- 2016/05/23 00:00 [accepted]
PHST- 2016/11/24 06:00 [entrez]
PHST- 2016/11/24 06:00 [pubmed]
PHST- 2016/11/24 06:01 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - jcav07p1926 [pii]
AID - 10.7150/jca.15603 [doi]
PST - epublish
SO  - J Cancer. 2016 Sep 27;7(14):1926-1938. doi: 10.7150/jca.15603. eCollection 2016.