PMID- 24890366
OWN - NLM
STAT- MEDLINE
DCOM- 20141104
LR  - 20211021
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 105
IP  - 8
DP  - 2014 Aug
TI  - Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1alpha/vascular 
      endothelial growth factor expression via inhibiting phosphatidylinositol 
      3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma 
      cells.
PG  - 1063-70
LID - 10.1111/cas.12458 [doi]
AB  - In multiple myeloma (MM), the hypoxic environment is an important factor causing 
      tumor angiogenesis, which is strongly correlated to disease progression and 
      unfavorable outcome by activating the key transcription factor, hypoxia-inducible 
      factor-1alpha (HIF-1alpha). Gambogic acid (GA) is the major active ingredient of gamboge, 
      which has been shown to possess antitumor effect by in vitro and in vivo study. 
      However, the underlying molecular mechanism of whether GA inhibits tumor 
      angiogenesis remains poorly understood. In this study, we investigated the 
      effects of GA on expression of HIF-1alpha, and its downstream target gene vascular 
      endothelial growth factor (VEGF) in human MM U266 cells. We found that hypoxia 
      induced increase in the level of HIF-1alpha subunit protein and activated the 
      phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target protein of rapamycin 
      (mTOR) pathway. Moreover, the treatment with GA markedly decreased HIF-1alpha and 
      VEGF expression under hypoxic conditions. Mechanistic studies exhibited that GA 
      inhibited the production of HIF-1alpha by reducing phosphorylation of Akt and mTOR in 
      U266 cells. Furthermore, in vivo study revealed that intravenous injection of GA 
      once every other day for 2 weeks could suppress tumor volumes by antiangiogenesis 
      activity. Taken together, our results identify that GA suppresses 
      hypoxia-activated pathways that are linked to MM progression, at least partly, by 
      the inhibition of the PI3K/Akt/mTOR signaling pathway. Therefore, GA may be a new 
      potent therapeutic agent against human MM cells.
CI  - (c) 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on 
      behalf of Japanese Cancer Association.
FAU - Wang, Fei
AU  - Wang F
AD  - Department of Hematology and Oncology (Key Department of Jiangsu Medicine), 
      Medical School, Zhongda Hospital, Southeast University, Nanjing, China.
FAU - Zhang, Wei
AU  - Zhang W
FAU - Guo, Liting
AU  - Guo L
FAU - Bao, Wen
AU  - Bao W
FAU - Jin, Nan
AU  - Jin N
FAU - Liu, Ran
AU  - Liu R
FAU - Liu, Ping
AU  - Liu P
FAU - Wang, Yonghui
AU  - Wang Y
FAU - Guo, Qinglong
AU  - Guo Q
FAU - Chen, Baoan
AU  - Chen B
LA  - eng
PT  - Journal Article
DEP - 20140727
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Xanthones)
RN  - 8N585K83U2 (gambogic acid)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Blotting, Western
MH  - Cell Hypoxia/*drug effects/physiology
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fluorescent Antibody Technique
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Multiple Myeloma/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Signal Transduction/*drug effects/physiology
MH  - Vascular Endothelial Growth Factor A/biosynthesis
MH  - Xanthones/*pharmacology
MH  - Xenograft Model Antitumor Assays
PMC - PMC4317858
OTO - NOTNLM
OT  - Angiogenesis
OT  - gambogic acid
OT  - hypoxia-inducible factor 1 alpha subunit
OT  - multiple myeloma
OT  - vascular endothelial growth factor A
EDAT- 2014/06/04 06:00
MHDA- 2014/11/05 06:00
PMCR- 2014/08/01
CRDT- 2014/06/04 06:00
PHST- 2014/03/18 00:00 [received]
PHST- 2014/05/26 00:00 [revised]
PHST- 2014/05/27 00:00 [accepted]
PHST- 2014/06/04 06:00 [entrez]
PHST- 2014/06/04 06:00 [pubmed]
PHST- 2014/11/05 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - 10.1111/cas.12458 [doi]
PST - ppublish
SO  - Cancer Sci. 2014 Aug;105(8):1063-70. doi: 10.1111/cas.12458. Epub 2014 Jul 27.