PMID- 22080879
OWN - NLM
STAT- MEDLINE
DCOM- 20120919
LR  - 20211203
IS  - 1525-1438 (Electronic)
IS  - 1048-891X (Linking)
VI  - 22
IP  - 1
DP  - 2012 Jan
TI  - LY294002 and metformin cooperatively enhance the inhibition of growth and the 
      induction of apoptosis of ovarian cancer cells.
PG  - 15-22
LID - 10.1097/IGC.0b013e3182322834 [doi]
AB  - BACKGROUND: 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.
FAU - Li, Cuilan
AU  - Li C
AD  - Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University 
      of Hong Kong, Hong Kong SAR, People's Republic of China.
FAU - Liu, Vincent Wing Sun
AU  - Liu VW
FAU - Chan, David Wai
AU  - Chan DW
FAU - Yao, Kwok Ming
AU  - Yao KM
FAU - Ngan, Hextan Yuen Sheung
AU  - Ngan HY
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Int J Gynecol Cancer
JT  - International journal of gynecological cancer : official journal of the 
      International Gynecological Cancer Society
JID - 9111626
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Chromones)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Proliferating Cell Nuclear Antigen)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (p27 antigen)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Acetyl-CoA Carboxylase/metabolism
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Apoptosis/*drug effects
MH  - Biomarkers, Tumor/metabolism
MH  - Blotting, Western
MH  - Caspase 3/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Chromones/*pharmacology/therapeutic use
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - Drug Synergism
MH  - Enzyme Inhibitors/*pharmacology/therapeutic use
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Metformin/*pharmacology/therapeutic use
MH  - Morpholines/*pharmacology/therapeutic use
MH  - Ovarian Neoplasms/*drug therapy/pathology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Proliferating Cell Nuclear Antigen/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tumor Suppressor Protein p53/metabolism
EDAT- 2011/11/15 06:00
MHDA- 2012/09/20 06:00
CRDT- 2011/11/15 06:00
PHST- 2011/11/15 06:00 [entrez]
PHST- 2011/11/15 06:00 [pubmed]
PHST- 2012/09/20 06:00 [medline]
AID - 10.1097/IGC.0b013e3182322834 [doi]
PST - ppublish
SO  - Int J Gynecol Cancer. 2012 Jan;22(1):15-22. doi: 10.1097/IGC.0b013e3182322834.