PMID- 12076959
OWN - NLM
STAT- MEDLINE
DCOM- 20020726
LR  - 20220311
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 962
DP  - 2002 May
TI  - NO-mediated chemoresistance in C6 glioma cells.
PG  - 8-17
AB  - Expression of inducible nitric oxide synthase (iNOS) in malignant glioma and 
      other tumors has been extensively documented. Massive production of NO by iNOS 
      has been shown to exert tumoricidal effects. However, NO may enhance vasodilation 
      and promote neovascularization, thereby facilitating tumor growth. Compared to 
      the effects of NO on tumor cell death and survival, correlation between NO and 
      cytotoxicity of chemotherapeutic reagents in glioma have been less well 
      characterized. Another gene product often linked to tumor malignancy is 
      hypoxia-inducible factor-1 (HIF-1). HIF-1 is a transcription factor that renders 
      malignant tumors adaptive to hypoxic stress during massive vascularization and 
      tumor invasion. Interestingly, HIF-1 also contributes to iNOS induction under 
      hypoxia. We have characterized the interrelationship between iNOS, HIF-1 and 
      chemoresistance. We note that increased NO synthesis by cytokine exposure or iNOS 
      overexpression neutralized the cytotoxicity of 
      1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 
      1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but not cisplatin, in rat C6 
      glioma cells. Both BCNU and CCNU are chloroethylnitrosoureas that kill tumor 
      cells via carbamoylating and alkylating actions. Further studies indicated that 
      iNOS only neutralized carbamoylating action of chloroethylnitrosoureas. 
      Expression of iNOS may inhibit HIF-1 activity under hypoxia in C6 glioma cells 
      transfected with a VEGF promoter-driven luciferase gene. Pretreatment of C6 cells 
      with N-acetyl-l-cysteine (NAC), an antioxidant, nullified the inhibitory effect 
      of iNOS on HIF-1 binding. That NO generated by iNOS expression inhibits HIF-1 
      activity in hypoxic C6 cells reveals a negative feedback loop in the HIF-1 --> 
      iNOS cascade. Together these results suggest a complicated role of NO in 
      malignant tumor growth, survival and invasion.
FAU - Yang, Ding-I
AU  - Yang DI
AD  - Department of Neurology and Center for the Study of Nervous System Injury, 
      Washington University School of Medicine, St. Louis, Missouri 63110, USA.
FAU - Yin, Jiu-Haw
AU  - Yin JH
FAU - Mishra, Snigdha
AU  - Mishra S
FAU - Mishra, Raj
AU  - Mishra R
FAU - Hsu, Chung Y
AU  - Hsu CY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (NOS2 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - U68WG3173Y (Carmustine)
SB  - IM
MH  - Animals
MH  - Carmustine/therapeutic use
MH  - DNA-Binding Proteins/metabolism
MH  - Drug Resistance, Neoplasm/*physiology
MH  - Glioblastoma/drug therapy/metabolism
MH  - Glioma/drug therapy/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Nitric Oxide/*metabolism
MH  - Nitric Oxide Synthase/metabolism
MH  - Nitric Oxide Synthase Type II
MH  - Nuclear Proteins/metabolism
MH  - *Transcription Factors
MH  - Tumor Cells, Cultured
RF  - 79
EDAT- 2002/06/22 10:00
MHDA- 2002/07/27 10:01
CRDT- 2002/06/22 10:00
PHST- 2002/06/22 10:00 [pubmed]
PHST- 2002/07/27 10:01 [medline]
PHST- 2002/06/22 10:00 [entrez]
AID - 10.1111/j.1749-6632.2002.tb04052.x [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2002 May;962:8-17. doi: 10.1111/j.1749-6632.2002.tb04052.x.