PMID- 18645006
OWN - NLM
STAT- MEDLINE
DCOM- 20080908
LR  - 20200930
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 7
IP  - 7
DP  - 2008 Jul
TI  - Hypoxia-induced resistance to anticancer drugs is associated with decreased 
      senescence and requires hypoxia-inducible factor-1 activity.
PG  - 1961-73
LID - 10.1158/1535-7163.MCT-08-0198 [doi]
AB  - Hypoxia in solid tumors is associated with the development of chemoresistance. 
      Although many studies have focused on the effect of hypoxia on drug-induced 
      apoptosis, the effect of nonapoptotic pathways on hypoxia-induced drug resistance 
      has not been previously investigated. Here, we determined the effects of hypoxia 
      on multiple forms of drug-induced death in human MDA-MB-231 breast carcinoma 
      cells. Clonogenic assays showed that preexposure to hypoxia leads to resistance 
      to various classes of chemotherapeutic agents, including anthracyclines 
      (daunorubicin and doxorubicin), epipodophyllotoxins (etoposide), and 
      anthracenediones (mitoxantrone). Results revealed a high degree of heterogeneity 
      in nuclear and cytoplasmic alterations in response to acute drug exposure; 
      however, the majority of exposed cells displayed morphologic and biochemical 
      changes consistent with drug-induced senescence. Hypoxia decreased only the 
      proportion of cells in the senescent population, whereas the small proportion of 
      cells exhibiting features of apoptosis or mitotic catastrophe were unaffected. 
      Similar results were obtained with human HCT116 colon carcinoma cells, indicating 
      that the protective effect of hypoxia on drug-induced senescence is not unique to 
      MDA-MB-231 cells. Treatment of MDA-MB-231 cells with small interfering RNA 
      targeting the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), a key 
      regulator of cellular adaptations to hypoxia, prevented hypoxia-induced 
      resistance. HIF-1alpha small interfering RNA also selectively abolished the 
      hypoxia-induced changes in the senescent population, indicating that the 
      increased survival was due to protection against drug-induced senescence. These 
      results support a requirement for HIF-1 in the adaptations leading to drug 
      resistance and reveal that decreased drug-induced senescence is also an important 
      contributor to the development of hypoxia-induced resistance.
FAU - Sullivan, Richard
AU  - Sullivan R
AD  - Department of Anatomy and Cell Biology, Queen's University, Botterell Hall, Room 
      859, Kingston, Ontario, Canada K7L 3N6.
FAU - Pare, Genevieve C
AU  - Pare GC
FAU - Frederiksen, Lisa J
AU  - Frederiksen LJ
FAU - Semenza, Gregg L
AU  - Semenza GL
FAU - Graham, Charles H
AU  - Graham CH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (RNA, Small Interfering)
RN  - 80168379AG (Doxorubicin)
RN  - H88EPA0A3N (Staurosporine)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Hypoxia/drug effects
MH  - Cell Line, Tumor
MH  - Cell Shape/drug effects
MH  - Cell Survival/drug effects
MH  - Cellular Senescence/*drug effects
MH  - Doxorubicin/pharmacology
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Phenotype
MH  - RNA, Small Interfering/metabolism
MH  - Staurosporine/pharmacology
MH  - Tumor Stem Cell Assay
EDAT- 2008/07/23 09:00
MHDA- 2008/09/09 09:00
CRDT- 2008/07/23 09:00
PHST- 2008/07/23 09:00 [pubmed]
PHST- 2008/09/09 09:00 [medline]
PHST- 2008/07/23 09:00 [entrez]
AID - 7/7/1961 [pii]
AID - 10.1158/1535-7163.MCT-08-0198 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2008 Jul;7(7):1961-73. doi: 10.1158/1535-7163.MCT-08-0198.