PMID- 16204076
OWN - NLM
STAT- MEDLINE
DCOM- 20051214
LR  - 20210807
IS  - 0008-5472 (Print)
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 19
DP  - 2005 Oct 1
TI  - Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit 
      hypoxia-inducible factor-1alpha accumulation and activity by disrupting 
      microtubule function.
PG  - 9021-8
AB  - We have recently identified a mechanistic link between disruption of the 
      microtubule cytoskeleton and inhibition of tumor angiogenesis via the 
      hypoxia-inducible factor-1 (HIF-1) pathway. Based on this model, we hypothesized 
      that other microtubule-targeting drugs may have a similar effect on HIF-1alpha. 
      To test that hypothesis, we studied the effects of different clinically relevant 
      microtubule-disrupting agents, including taxotere, epothilone B, discodermolide, 
      vincristine, 2-methoxyestradiol, and colchicine. In all cases, HIF-1alpha 
      protein, but not mRNA, was down-regulated in a drug dose-dependent manner. In 
      addition, HIF-1alpha transcriptional activity was also inhibited by all drugs 
      tested. To further examine whether these effects were dependent on microtubule 
      network disruption, we tested the ability of epothilone B to inhibit HIF-1alpha 
      protein in the human ovarian cancer cell line 1A9 and its beta-tubulin mutant 
      epothilone-resistant subclone 1A9/A8. Our data showed that epothilone B treatment 
      down-regulated HIF-1alpha protein in the parental 1A9 cells but had no effect in 
      the resistant 1A9/A8 cells. These observations were confirmed by confocal 
      microscopy, which showed impaired nuclear accumulation of HIF-1alpha in parental 
      1A9 cells at epothilone B concentrations that induced extensive microtubule 
      stabilization. In contrast, epothilone B treatment had no effect on either 
      microtubules or HIF-1alpha nuclear accumulation in the resistant 1A9/A8 cells. 
      Furthermore, epothilone B inhibited HIF-1 transcriptional activity in 1A9 cells, 
      as evidenced by a hypoxia response element-luciferase reporter assay, but had no 
      effect on HIF-1 activity in the resistant 1A9/A8 cells. These data directly link 
      beta-tubulin drug binding with HIF-1alpha protein inhibition. Our results further 
      provide a strong rationale for testing taxanes and epothilones in clinical trials 
      targeting HIF-1 in cancer patients.
FAU - Escuin, Daniel
AU  - Escuin D
AD  - Department of Hematology and Oncology, Winship Cancer Institute, Robert Woodruff 
      Health Sciences Center, Emory University School of Medicine, Atlanta, Georgia 
      30322, USA.
FAU - Kline, Erik R
AU  - Kline ER
FAU - Giannakakou, Paraskevi
AU  - Giannakakou P
LA  - eng
GR  - R01 CA086335/CA/NCI NIH HHS/United States
GR  - T32 CA062948/CA/NCI NIH HHS/United States
GR  - R01 CA86335/CA/NCI NIH HHS/United States
GR  - UL1 TR002384/TR/NCATS NIH HHS/United States
GR  - R01 CA100202/CA/NCI NIH HHS/United States
GR  - 1R01 CA100202-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Alkaloids)
RN  - 0 (Alkanes)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Carbamates)
RN  - 0 (Epothilones)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Lactones)
RN  - 0 (Pyrones)
RN  - 0 (Taxoids)
RN  - 15H5577CQD (Docetaxel)
RN  - 4TI98Z838E (Estradiol)
RN  - 5J49Q6B70F (Vincristine)
RN  - 6I2QW73SR5 (2-Methoxyestradiol)
RN  - DHG59994DN (discodermolide)
RN  - SML2Y3J35T (Colchicine)
RN  - UEC0H0URSE (epothilone B)
SB  - IM
MH  - 2-Methoxyestradiol
MH  - Alkaloids/*pharmacology
MH  - Alkanes/pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Carbamates/pharmacology
MH  - Cell Line, Tumor
MH  - Colchicine/pharmacology
MH  - Docetaxel
MH  - Down-Regulation/drug effects
MH  - Epothilones/pharmacology
MH  - Estradiol/analogs & derivatives/pharmacology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism
MH  - Lactones/pharmacology
MH  - Microtubules/*drug effects/metabolism/physiology
MH  - Pyrones/pharmacology
MH  - Taxoids/pharmacology
MH  - Vincristine/pharmacology
PMC - PMC6623969
MID - NIHMS100160
EDAT- 2005/10/06 09:00
MHDA- 2005/12/15 09:00
PMCR- 2019/07/11
CRDT- 2005/10/06 09:00
PHST- 2005/10/06 09:00 [pubmed]
PHST- 2005/12/15 09:00 [medline]
PHST- 2005/10/06 09:00 [entrez]
PHST- 2019/07/11 00:00 [pmc-release]
AID - 65/19/9021 [pii]
AID - 10.1158/0008-5472.CAN-04-4095 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Oct 1;65(19):9021-8. doi: 10.1158/0008-5472.CAN-04-4095.