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Article: LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells
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TitleLY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells
 
AuthorsLi, C1
Liu, VWS1
Chan, DW1
Yao, KM1
Ngan, HYS1
 
KeywordsAKT
AMPK
LY294002
Metformin
MTOR
Ovarian cancer
 
Issue Date2012
 
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.ijgc.net/
 
CitationInternational Journal of Gynecological Cancer, 2012, v. 22 n. 1, p. 15-22 [How to Cite?]
DOI: http://dx.doi.org/10.1097/IGC.0b013e3182322834
 
AbstractBackground: The phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently aberrantly activated in ovarian cancer and confers the chemoresistant phenotype of ovarian cancer cells. LY294002 (PI3K inhibitor) and metformin (5′-adenosine monophosphate [AMP]-activated protein kinase [AMPK] activator) are 2 drugs that were known to inhibit mTOR expression through the AKT-dependent and AKT-independent pathways, respectively. In this study, we explored the effectiveness of LY294002 and metformin in combination on inhibition of ovarian cancer cell growth. Methods: Western blotting was used to detect the changes of PI3K/AKT/mTOR and AMPK/acetyl-CoA carboxylase (ACC) signaling activities, cell cycle control, and apoptosis. Cell growth was evaluated by cell proliferation, colony formation, and soft agar assays. Flow cytometry was used to study cell cycle distribution and cell death upon drug treatment. Results: Our study showed that LY294002 and metformin in combination could simultaneously enhance the repression of the PI3K/AKT/mTOR pathway and the activation of the AMPK/ACC pathway. The downstream target of AKT and AMPK, mTOR, was cooperatively repressed when the drugs were used together. The cell cycle regulatory factors, p53, p27, and p21, were up-regulated. On the other hand, caspase 3 and poly (ADP-ribose) polymerase activities involved in apoptosis were also activated. Cell growth assays indicated that LY294002 and metformin could effectively inhibit ovarian cancer cell growth. Flow cytometry analysis showed that the treatment of the 2 drugs mentioned above induced cell cycle arrest at G1 phase and increased sub-G1 apoptotic cells. Conclusion: The combinational use of LY294002 and metformin can enhance inhibition of the growth and induction of the apoptosis of ovarian cancer cells. Our results may provide significant insight into the future therapeutic regimens in ovarian cancer. Copyright © 2012 by IGCS and ESGO.
 
ISSN1048-891X
2013 Impact Factor: 1.949
 
DOIhttp://dx.doi.org/10.1097/IGC.0b013e3182322834
 
ISI Accession Number IDWOS:000298628800005
Funding AgencyGrant Number
Wong Check She Charitable Foundation
Funding Information:

This study was generously supported by the Wong Check She Charitable Foundation.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLi, C
 
dc.contributor.authorLiu, VWS
 
dc.contributor.authorChan, DW
 
dc.contributor.authorYao, KM
 
dc.contributor.authorNgan, HYS
 
dc.date.accessioned2011-11-24T10:03:25Z
 
dc.date.available2011-11-24T10:03:25Z
 
dc.date.issued2012
 
dc.description.abstractBackground: The phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently aberrantly activated in ovarian cancer and confers the chemoresistant phenotype of ovarian cancer cells. LY294002 (PI3K inhibitor) and metformin (5′-adenosine monophosphate [AMP]-activated protein kinase [AMPK] activator) are 2 drugs that were known to inhibit mTOR expression through the AKT-dependent and AKT-independent pathways, respectively. In this study, we explored the effectiveness of LY294002 and metformin in combination on inhibition of ovarian cancer cell growth. Methods: Western blotting was used to detect the changes of PI3K/AKT/mTOR and AMPK/acetyl-CoA carboxylase (ACC) signaling activities, cell cycle control, and apoptosis. Cell growth was evaluated by cell proliferation, colony formation, and soft agar assays. Flow cytometry was used to study cell cycle distribution and cell death upon drug treatment. Results: Our study showed that LY294002 and metformin in combination could simultaneously enhance the repression of the PI3K/AKT/mTOR pathway and the activation of the AMPK/ACC pathway. The downstream target of AKT and AMPK, mTOR, was cooperatively repressed when the drugs were used together. The cell cycle regulatory factors, p53, p27, and p21, were up-regulated. On the other hand, caspase 3 and poly (ADP-ribose) polymerase activities involved in apoptosis were also activated. Cell growth assays indicated that LY294002 and metformin could effectively inhibit ovarian cancer cell growth. Flow cytometry analysis showed that the treatment of the 2 drugs mentioned above induced cell cycle arrest at G1 phase and increased sub-G1 apoptotic cells. Conclusion: The combinational use of LY294002 and metformin can enhance inhibition of the growth and induction of the apoptosis of ovarian cancer cells. Our results may provide significant insight into the future therapeutic regimens in ovarian cancer. Copyright © 2012 by IGCS and ESGO.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationInternational Journal of Gynecological Cancer, 2012, v. 22 n. 1, p. 15-22 [How to Cite?]
DOI: http://dx.doi.org/10.1097/IGC.0b013e3182322834
 
dc.identifier.doihttp://dx.doi.org/10.1097/IGC.0b013e3182322834
 
dc.identifier.epage22
 
dc.identifier.hkuros197744
 
dc.identifier.isiWOS:000298628800005
Funding AgencyGrant Number
Wong Check She Charitable Foundation
Funding Information:

This study was generously supported by the Wong Check She Charitable Foundation.

 
dc.identifier.issn1048-891X
2013 Impact Factor: 1.949
 
dc.identifier.issue1
 
dc.identifier.openurl
 
dc.identifier.pmid22080879
 
dc.identifier.scopuseid_2-s2.0-84863229883
 
dc.identifier.spage15
 
dc.identifier.urihttp://hdl.handle.net/10722/143365
 
dc.identifier.volume22
 
dc.languageeng
 
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.ijgc.net/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofInternational Journal of Gynecological Cancer
 
dc.relation.referencesReferences in Scopus
 
dc.rightsThe definitive version is available at www.blackwell-synergy.com
 
dc.subjectAKT
 
dc.subjectAMPK
 
dc.subjectLY294002
 
dc.subjectMetformin
 
dc.subjectMTOR
 
dc.subjectOvarian cancer
 
dc.titleLY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine