PMID- 19671732
OWN - NLM
STAT- MEDLINE
DCOM- 20100119
LR  - 20200930
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 8
IP  - 8
DP  - 2009 Aug
TI  - Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of 
      multiple myeloma cells to melphalan.
PG  - 2329-38
LID - 10.1158/1535-7163.MCT-09-0150 [doi]
AB  - Abnormal activation of hypoxia-inducible factor-1 (HIF-1), one of the most 
      important transcription factors for the adaptation of cells to hypoxia, is 
      frequently observed in numerous types of solid tumors. Dysregulation of HIF-1 
      induces tumor angiogenesis and enhances the expression of anti-apoptotic proteins 
      and glycolysis-associated enzymes in cancer cells, which in turn leads to the 
      promotion of tumor growth. In the present study, we examined the pathophysiologic 
      role of HIF-1 in multiple myeloma. Furthermore, we explored the possibility that 
      HIF-1 may be a molecular target for myeloma therapy. We identified constitutive 
      expression of the hypoxia-inducible factor-1 alpha (HIF-1alpha)-subunit in 
      established myeloma cell lines and in primary myeloma cells. Treatment with 
      insulin-like growth factor-1 (IGF-1) significantly increased HIF-1alpha 
      expression through activation of the AKT and mitogen-activated protein kinase 
      signaling pathways. Inhibition of HIF-1 function either by echinomycin, a 
      specific HIF-1 inhibitor, or a siRNA against HIF-1alpha resulted in enhanced 
      sensitivity to melphalan in myeloma cells. This inhibition of HIF-1 also reversed 
      the protective effect of IGF-1 on melphalan-induced apoptosis. Inhibition of 
      HIF-1 drastically reduced both basal and IGF-1-induced expression of survivin, 
      one of the most important anti-apoptotic proteins in myeloma cells. We conclude 
      that HIF-1 inhibition may be an attractive therapeutic strategy for multiple 
      myeloma.
FAU - Hu, Yongzhen
AU  - Hu Y
AD  - Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
FAU - Kirito, Keita
AU  - Kirito K
FAU - Yoshida, Kozue
AU  - Yoshida K
FAU - Mitsumori, Toru
AU  - Mitsumori T
FAU - Nakajima, Kei
AU  - Nakajima K
FAU - Nozaki, Yumi
AU  - Nozaki Y
FAU - Hamanaka, Satoshi
AU  - Hamanaka S
FAU - Nagashima, Takahiro
AU  - Nagashima T
FAU - Kunitama, Masae
AU  - Kunitama M
FAU - Sakoe, Kumi
AU  - Sakoe K
FAU - Komatsu, Norio
AU  - Komatsu N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090811
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antigens, CD19)
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (RNA, Small Interfering)
RN  - 512-64-1 (Echinomycin)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - Q41OR9510P (Melphalan)
SB  - IM
MH  - Antigens, CD19/metabolism
MH  - Antineoplastic Agents, Alkylating/*pharmacology
MH  - Apoptosis
MH  - Cell Line, Tumor
MH  - Echinomycin/pharmacology
MH  - Fluorescent Antibody Technique
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*antagonists & inhibitors/metabolism
MH  - Insulin-Like Growth Factor I/metabolism
MH  - Melphalan/*pharmacology
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Multiple Myeloma/*drug therapy/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - RNA, Small Interfering/metabolism
EDAT- 2009/08/13 09:00
MHDA- 2010/01/20 06:00
CRDT- 2009/08/13 09:00
PHST- 2009/08/13 09:00 [entrez]
PHST- 2009/08/13 09:00 [pubmed]
PHST- 2010/01/20 06:00 [medline]
AID - 1535-7163.MCT-09-0150 [pii]
AID - 10.1158/1535-7163.MCT-09-0150 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2009 Aug;8(8):2329-38. doi: 10.1158/1535-7163.MCT-09-0150. Epub 
      2009 Aug 11.