PMID- 22938093
OWN - NLM
STAT- MEDLINE
DCOM- 20130116
LR  - 20211021
IS  - 1520-6025 (Electronic)
IS  - 0163-3864 (Print)
IS  - 0163-3864 (Linking)
VI  - 75
IP  - 9
DP  - 2012 Sep 28
TI  - Structures and mechanisms of antitumor agents: xestoquinones uncouple cellular 
      respiration and disrupt HIF signaling in human breast tumor cells.
PG  - 1553-9
AB  - The organic extract of a marine sponge, Petrosia alfiani, selectively inhibited 
      iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in a human 
      breast tumor T47D cell-based reporter assay. Bioassay-guided fractionation 
      yielded seven xestoquinones (1-7) including three new compounds: 
      14-hydroxymethylxestoquinone (1), 15-hydroxymethylxestoquinone (2), and 
      14,15-dihydroxestoquinone (3). Compounds 1-7 were evaluated for their effects on 
      HIF-1 signaling, mitochondrial respiration, and tumor cell 
      proliferation/viability. The known metabolites adociaquinones A (5) and B (6), 
      which possess a 3,4-dihydro-2H-1,4-thiazine-1,1-dioxide moiety, potently and 
      selectively inhibited iron chelator-induced HIF-1 activation in T47D cells, each 
      with an IC(50) value of 0.2 muM. Mechanistic studies revealed that adociaquinones 
      promote oxygen consumption without affecting mitochondrial membrane potential. 
      Compound 1 both enhances respiration and decreases mitochondrial membrane 
      potential, suggesting that it acts as a protonophore that uncouples mitochondrial 
      respiration.
FAU - Du, Lin
AU  - Du L
AD  - Department of Pharmacognosy, School of Pharmacy, University of Mississippi, 
      University, Mississippi 38677, USA.
FAU - Mahdi, Fakhri
AU  - Mahdi F
FAU - Datta, Sandipan
AU  - Datta S
FAU - Jekabsons, Mika B
AU  - Jekabsons MB
FAU - Zhou, Yu-Dong
AU  - Zhou YD
FAU - Nagle, Dale G
AU  - Nagle DG
LA  - eng
GR  - C06 RR014503/RR/NCRR NIH HHS/United States
GR  - R01 CA098787/CA/NCI NIH HHS/United States
GR  - R56 CA098787/CA/NCI NIH HHS/United States
GR  - CA98787/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120831
PL  - United States
TA  - J Nat Prod
JT  - Journal of natural products
JID - 7906882
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Iron Chelating Agents)
RN  - 0 (Quinones)
RN  - 97743-96-9 (xestoquinone)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/chemistry/*isolation & purification/*pharmacology
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*antagonists & inhibitors
MH  - Inhibitory Concentration 50
MH  - Iron Chelating Agents/pharmacology
MH  - Marine Biology
MH  - Mitochondria/drug effects/metabolism
MH  - Molecular Structure
MH  - Porifera/*chemistry
MH  - Quinones/chemistry/*isolation & purification/*pharmacology
PMC - PMC3482980
MID - NIHMS405178
EDAT- 2012/09/04 06:00
MHDA- 2013/01/17 06:00
PMCR- 2013/09/28
CRDT- 2012/09/04 06:00
PHST- 2012/09/04 06:00 [entrez]
PHST- 2012/09/04 06:00 [pubmed]
PHST- 2013/01/17 06:00 [medline]
PHST- 2013/09/28 00:00 [pmc-release]
AID - 10.1021/np3002892 [doi]
PST - ppublish
SO  - J Nat Prod. 2012 Sep 28;75(9):1553-9. doi: 10.1021/np3002892. Epub 2012 Aug 31.