PMID- 21875114
OWN - NLM
STAT- MEDLINE
DCOM- 20111128
LR  - 20211020
IS  - 1520-6025 (Electronic)
IS  - 0163-3864 (Print)
IS  - 0163-3864 (Linking)
VI  - 74
IP  - 9
DP  - 2011 Sep 23
TI  - Mitochondrial respiration inhibitors suppress protein translation and hypoxic 
      signaling via the hyperphosphorylation and inactivation of translation initiation 
      factor eIF2alpha and elongation factor eEF2.
PG  - 1894-901
LID - 10.1021/np200370z [doi]
AB  - Over 20,000 lipid extracts of plants and marine organisms were evaluated in a 
      human breast tumor T47D cell-based reporter assay for hypoxia-inducible factor-1 
      (HIF-1) inhibitory activity. Bioassay-guided isolation and dereplication-based 
      structure elucidation of an active extract from the Bael tree (Aegle marmelos) 
      afforded two protolimonoids, skimmiarepin A (1) and skimmiarepin C (2). In T47D 
      cells, 1 and 2 inhibited hypoxia-induced HIF-1 activation with IC50 values of 
      0.063 and 0.068 muM, respectively. Compounds 1 and 2 also suppressed hypoxic 
      induction of the HIF-1 target genes GLUT-1 and VEGF. Mechanistic studies revealed 
      that 1 and 2 inhibited HIF-1 activation by blocking the hypoxia-induced 
      accumulation of HIF-1alpha protein. At the range of concentrations that inhibited 
      HIF-1 activation, 1 and 2 suppressed cellular respiration by selectively 
      inhibiting the mitochondrial electron transport chain at complex I (NADH 
      dehydrogenase). Further investigation indicated that mitochondrial respiration 
      inhibitors such as 1 and rotenone induced the rapid hyperphosphorylation and 
      inhibition of translation initiation factor eIF2alpha and elongation factor eEF2. The 
      inhibition of protein translation may account for the short-term exposure effects 
      exerted by mitochondrial inhibitors on cellular signaling, while the suppression 
      of cellular ATP production may contribute to the inhibitory effects following 
      extended treatment periods.
FAU - Li, Jun
AU  - Li J
AD  - Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, 
      School of Pharmacy, University of Mississippi, University, Mississippi 38677, 
      United States.
FAU - Mahdi, Fakhri
AU  - Mahdi F
FAU - Du, Lin
AU  - Du L
FAU - Datta, Sandipan
AU  - Datta S
FAU - Nagle, Dale G
AU  - Nagle DG
FAU - Zhou, Yu-Dong
AU  - Zhou YD
LA  - eng
GR  - R01 CA098787-06/CA/NCI NIH HHS/United States
GR  - C06 RR014503/RR/NCRR NIH HHS/United States
GR  - CA98787/CA/NCI NIH HHS/United States
GR  - C06 RR-14503-01/RR/NCRR NIH HHS/United States
GR  - R01 CA098787/CA/NCI NIH HHS/United States
GR  - R01 CA098787-07/CA/NCI NIH HHS/United States
GR  - R56 CA098787/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110829
PL  - United States
TA  - J Nat Prod
JT  - Journal of natural products
JID - 7906882
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Limonins)
RN  - 0 (Triterpenes)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (skimmiarepin A)
RN  - 0 (skimmiarepin C)
RN  - EC 1.6.99.3 (NADH Dehydrogenase)
SB  - IM
MH  - Aegle/*chemistry
MH  - Endoplasmic Reticulum/metabolism
MH  - Eukaryotic Initiation Factor-2/*antagonists & inhibitors
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*antagonists & inhibitors
MH  - Indonesia
MH  - Limonins
MH  - Mitochondria/*metabolism
MH  - Molecular Structure
MH  - NADH Dehydrogenase/antagonists & inhibitors
MH  - Respiration/*drug effects
MH  - Triterpenes/chemistry/*isolation & purification/*pharmacology
MH  - Vascular Endothelial Growth Factor A/antagonists & inhibitors/genetics
PMC - PMC3179826
MID - NIHMS321582
EDAT- 2011/08/31 06:00
MHDA- 2011/12/13 00:00
PMCR- 2012/09/23
CRDT- 2011/08/31 06:00
PHST- 2011/08/31 06:00 [entrez]
PHST- 2011/08/31 06:00 [pubmed]
PHST- 2011/12/13 00:00 [medline]
PHST- 2012/09/23 00:00 [pmc-release]
AID - 10.1021/np200370z [doi]
PST - ppublish
SO  - J Nat Prod. 2011 Sep 23;74(9):1894-901. doi: 10.1021/np200370z. Epub 2011 Aug 29.