PMID- 22684842
OWN - NLM
STAT- MEDLINE
DCOM- 20131223
LR  - 20171116
IS  - 1573-675X (Electronic)
IS  - 1360-8185 (Linking)
VI  - 17
IP  - 9
DP  - 2012 Sep
TI  - Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK 
      activity in HCT116 colon cancer.
PG  - 938-49
LID - 10.1007/s10495-012-0719-0 [doi]
AB  - Tumor hypoxia is considered the best validated target in clinical oncology 
      because of its significant contribution to chemotherapy failure and drug 
      resistance. As an approach to target hypoxia, we assessed the potential of 
      quercetin, a flavonoid widely distributed in plants, as a anticancer agent under 
      hypoxic conditions and examined its pharmacological mechanisms by primarily 
      focusing on the role of AMP-activated protein kinase (AMPK). Quercetin 
      significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model 
      with a substantial reduction of AMPK activity. In a cell culture system, 
      quercetin more dramatically induced apoptosis of HCT116 cancer cells under 
      hypoxic conditions than normoxic conditions, and this was tightly associated with 
      inhibition of hypoxia-induced AMPK activity. An in vitro kinase assay 
      demonstrated that quercetin directly inhibits AMPK activity. Inhibition of AMPK 
      by expressing a dominant-negative form resulted in an increase of apoptosis under 
      hypoxia, and a constitutively active form of AMPK effectively blocked 
      quercetin-induced apoptosis under hypoxia. Collectively, our data suggest that 
      quercetin directly inhibits hypoxia-induced AMPK, which plays a protective role 
      against hypoxia. Quercetin also reduced the activity of hypoxia-inducible 
      factor-1 (HIF-1), a major transcription factor for adaptive cellular response to 
      hypoxia. Moreover, quercetin sensitized HCT116 cancer cells to the anticancer 
      drugs cisplatin and etoposide under hypoxic conditions. Our findings suggest that 
      AMPK may serve as a novel target for overcoming tumor hypoxia-associated negative 
      aspects.
FAU - Kim, Hak-Su
AU  - Kim HS
AD  - Department of Biochemistry and Molecular Biology, Medical Research Center and 
      Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, 
      130-701, Korea.
FAU - Wannatung, Tirawat
AU  - Wannatung T
FAU - Lee, Sooho
AU  - Lee S
FAU - Yang, Woo Kyeom
AU  - Yang WK
FAU - Chung, Sung Hyun
AU  - Chung SH
FAU - Lim, Jong-Seok
AU  - Lim JS
FAU - Choe, Wonchae
AU  - Choe W
FAU - Kang, Insug
AU  - Kang I
FAU - Kim, Sung-Soo
AU  - Kim SS
FAU - Ha, Joohun
AU  - Ha J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Apoptosis
JT  - Apoptosis : an international journal on programmed cell death
JID - 9712129
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antioxidants)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 9IKM0I5T1E (Quercetin)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - AMP-Activated Protein Kinases/*antagonists & inhibitors
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Antioxidants/pharmacology
MH  - Apoptosis/*drug effects
MH  - Cell Hypoxia/*drug effects
MH  - Cell Line, Tumor
MH  - Cisplatin/pharmacology
MH  - Colonic Neoplasms/*drug therapy
MH  - Etoposide/pharmacology
MH  - Genes, Reporter
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Quercetin/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/06/12 06:00
MHDA- 2013/12/24 06:00
CRDT- 2012/06/12 06:00
PHST- 2012/06/12 06:00 [entrez]
PHST- 2012/06/12 06:00 [pubmed]
PHST- 2013/12/24 06:00 [medline]
AID - 10.1007/s10495-012-0719-0 [doi]
PST - ppublish
SO  - Apoptosis. 2012 Sep;17(9):938-49. doi: 10.1007/s10495-012-0719-0.