PMID- 24416349
OWN - NLM
STAT- MEDLINE
DCOM- 20140902
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 1
DP  - 2014
TI  - The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects 
      against PTEN mutant gastric cancer cells: involvement of MAPK-dependent 
      autophagic, but not apoptotic cell death pathway.
PG  - e85116
LID - 10.1371/journal.pone.0085116 [doi]
LID - e85116
AB  - In the current study, we showed that the combination of mammalian target of 
      rapamycin (mTOR) inhibitor RAD001 (everolimus) and Akt inhibitor MK-2206 exerted 
      synergistic cytotoxic effects against low-phosphatase and tensin homolog (PTEN) 
      gastric cancer cells (HGC-27 and SNU-601 lines). In HGC-27 cells, RAD001 and 
      MK-2206 synergistically induced G1/S cell cycle arrest, growth inhibition, cell 
      death but not apoptosis. RAD001 and MK-2206 synergistically induced light chain 
      3B (LC3B) and beclin-1 expression, two important autophagy indicators. Meanwhile, 
      the autophagy inhibitor 3-methyladenine (3-MA) and chloroquine inhibited the 
      cytotoxic effects by RAD001 and MK-2206, suggesting that autophagic, but not 
      apoptotic cell death was important for the cytotoxic effects by the 
      co-administration. We observed that the combination of RAD001 and MK-2206 exerted 
      enhanced effects on Akt/mTOR inhibition, cyclin D1 down-regulation and 
      ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinases) 
      activation. Intriguingly, MEK/ERK inhibitors PD98059 and U0126 suppressed RAD001 
      plus MK-2206-induced beclin-1 expression, autophagy induction and cytotoxicity in 
      HGC-27 cells. In conclusion, these results suggested that the synergistic 
      anti-gastric cancer cells ability by RAD001 and MK-2206 involves ERK-dependent 
      autophagic cell death pathway.
FAU - Ji, Dongmei
AU  - Ji D
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Zhang, Zhe
AU  - Zhang Z
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Cheng, Lei
AU  - Cheng L
AD  - Department of Interventional Radiology, Suzhou Hospital Affiliated to Nanjing 
      Medical University, Suzhou, Jiangsu, China.
FAU - Chang, Jinjia
AU  - Chang J
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Wang, Shanshan
AU  - Wang S
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Zheng, Biqiang
AU  - Zheng B
AD  - Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai 
      Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
FAU - Zheng, Rongliang
AU  - Zheng R
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Sun, Zuojun
AU  - Sun Z
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Wang, Chenchen
AU  - Wang C
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Zhang, Zhiqing
AU  - Zhang Z
AD  - Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
FAU - Liu, Rujiao
AU  - Liu R
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Zhang, Xiaowei
AU  - Zhang X
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Liu, Xin
AU  - Liu X
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Wang, Xiaofeng
AU  - Wang X
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
FAU - Li, Jin
AU  - Li J
AD  - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 
      Medical College, Fudan University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140109
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BECN1 protein, human)
RN  - 0 (Beclin-1)
RN  - 0 (Butadienes)
RN  - 0 (CCND1 protein, human)
RN  - 0 (Flavonoids)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (MAP1LC3B protein, human)
RN  - 0 (MK 2206)
RN  - 0 (Membrane Proteins)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Nitriles)
RN  - 0 (U 0126)
RN  - 136601-57-5 (Cyclin D1)
RN  - 5142-23-4 (3-methyladenine)
RN  - 886U3H6UFF (Chloroquine)
RN  - 9HW64Q8G6G (Everolimus)
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 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - JAC85A2161 (Adenine)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenine/analogs & derivatives/pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis
MH  - Apoptosis Regulatory Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Autophagy/*drug effects
MH  - Beclin-1
MH  - Butadienes/pharmacology
MH  - Cell Line, Tumor
MH  - Chloroquine/pharmacology
MH  - Cyclin D1/antagonists & inhibitors/genetics/metabolism
MH  - Drug Synergism
MH  - Everolimus
MH  - Flavonoids/pharmacology
MH  - Gastric Mucosa/drug effects/metabolism/pathology
MH  - *Gene Expression Regulation, Neoplastic
MH  - Heterocyclic Compounds, 3-Ring/*pharmacology
MH  - Humans
MH  - Membrane Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Microtubule-Associated Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*genetics/metabolism
MH  - Nitriles/pharmacology
MH  - PTEN Phosphohydrolase/antagonists & inhibitors/*genetics/metabolism
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
PMC - PMC3887024
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/01/15 06:00
MHDA- 2014/09/03 06:00
PMCR- 2014/01/09
CRDT- 2014/01/14 06:00
PHST- 2013/01/15 00:00 [received]
PHST- 2013/11/30 00:00 [accepted]
PHST- 2014/01/14 06:00 [entrez]
PHST- 2014/01/15 06:00 [pubmed]
PHST- 2014/09/03 06:00 [medline]
PHST- 2014/01/09 00:00 [pmc-release]
AID - PONE-D-13-02403 [pii]
AID - 10.1371/journal.pone.0085116 [doi]
PST - epublish
SO  - PLoS One. 2014 Jan 9;9(1):e85116. doi: 10.1371/journal.pone.0085116. eCollection 
      2014.