PMID- 20066420
OWN - NLM
STAT- MEDLINE
DCOM- 20100908
LR  - 20211020
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 66
IP  - 5
DP  - 2010 Oct
TI  - Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting 
      hypoxia-inducible factor 1alpha.
PG  - 899-911
LID - 10.1007/s00280-009-1238-8 [doi]
AB  - PURPOSE: Hypoxic tumor cells overexpressing hypoxia-inducible factor 1alpha 
      (HIF-1alpha) are generally resistant to chemo/radiotherapy. We have reported that 
      Se-methylselenocysteine (MSC) therapeutically enhances the efficacy and 
      selectivity of irinotecan against human tumor xenografts. The aim of this study 
      was to delineate the mechanism responsible for the observed efficacy targeting on 
      HIF-1alpha and its transcriptionally regulated genes VEGF and CAIX. METHODS: We 
      investigated the mechanism of HIF-1alpha inhibition by MSC and its critical role 
      in the therapeutic outcome by generating HIF-1alpha stable knockdown (KD) human 
      head and neck squamous cell carcinoma, FaDu by transfecting HIF-1alpha short 
      hairpin RNA. RESULTS: While cytotoxic efficacy in combination with methylselenic 
      acid (MSA) with SN-38 (active metabolites of MSC and irinotecan) could not be 
      confirmed in vitro against normoxic tumor cells, the hypoxic tumor cells were 
      more sensitive to the combination. Reduction in HIF-1alpha either by MSA or shRNA 
      knockdown resulted in significant increase in cytotoxicity of SN38 in vitro 
      against hypoxic, but not the normoxic tumor cells. Similarly, in vivo, either MSC 
      in combination with irinotecan treatment of parental xenografts or HIF-1alpha KD 
      tumors treated with irinotecan alone resulted in comparable therapeutic response 
      and increase in the long-term survival of mice bearing FaDu xenografts. 
      CONCLUSIONS: Our results show that HIF-1alpha is a critical target for MSC and 
      its inhibition was associated with enhanced antitumor activity of irinotecan. 
      Inhibition of HIF-1alpha appeared to be mediated through stabilization of PHD2, 3 
      and downregulation of ROS by MSC. Thus, our findings support the development of 
      MSC as a HIF-1alpha inhibitor in combination chemotherapy.
FAU - Chintala, Sreenivasulu
AU  - Chintala S
AD  - Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, 
      USA. sreenivasulu.chintala@roswellpark.org
FAU - Toth, Karoly
AU  - Toth K
FAU - Cao, Shousong
AU  - Cao S
FAU - Durrani, Farukh A
AU  - Durrani FA
FAU - Vaughan, Mary M
AU  - Vaughan MM
FAU - Jensen, Randy L
AU  - Jensen RL
FAU - Rustum, Youcef M
AU  - Rustum YM
LA  - eng
GR  - P30 CA016056/CA/NCI NIH HHS/United States
GR  - R21 CA133682/CA/NCI NIH HHS/United States
GR  - CA 016056/CA/NCI NIH HHS/United States
GR  - 1R21CA133682-01A2/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100112
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Organoselenium Compounds)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0CH9049VIS (Selenocysteine)
RN  - 7673326042 (Irinotecan)
RN  - EC 4.2.1.1 (CA9 protein, human)
RN  - EC 4.2.1.1 (Carbonic Anhydrase IX)
RN  - EC 4.2.1.1 (Carbonic Anhydrases)
RN  - K848JZ4886 (Cysteine)
RN  - TWK220499Z (selenomethylselenocysteine)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Animals
MH  - Antigens, Neoplasm/genetics
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Camptothecin/administration & dosage/analogs & derivatives
MH  - Carbonic Anhydrase IX
MH  - Carbonic Anhydrases/genetics
MH  - Carcinoma, Squamous Cell/*drug therapy/genetics
MH  - Cell Hypoxia
MH  - Cysteine/administration & dosage/analogs & derivatives
MH  - *Drug Delivery Systems
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Head and Neck Neoplasms/*drug therapy/genetics
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/genetics
MH  - Irinotecan
MH  - Mice
MH  - Mice, Nude
MH  - Organoselenium Compounds/administration & dosage
MH  - RNA, Small Interfering/administration & dosage
MH  - Reactive Oxygen Species/metabolism
MH  - Selenocysteine/analogs & derivatives
MH  - Vascular Endothelial Growth Factor A/genetics
MH  - Xenograft Model Antitumor Assays
PMC - PMC2916970
MID - NIHMS190204
EDAT- 2010/01/13 06:00
MHDA- 2010/09/09 06:00
PMCR- 2011/10/01
CRDT- 2010/01/13 06:00
PHST- 2009/10/06 00:00 [received]
PHST- 2009/12/26 00:00 [accepted]
PHST- 2010/01/13 06:00 [entrez]
PHST- 2010/01/13 06:00 [pubmed]
PHST- 2010/09/09 06:00 [medline]
PHST- 2011/10/01 00:00 [pmc-release]
AID - 10.1007/s00280-009-1238-8 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2010 Oct;66(5):899-911. doi: 
      10.1007/s00280-009-1238-8. Epub 2010 Jan 12.