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.

Abstract

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.

• Authors: Dongmei Ji, Zhe Zhang, Lei Cheng, Jinjia Chang, Shanshan Wang, Biqiang Zheng, Rongliang Zheng, Zuojun Sun, Chenchen Wang, Zhiqing Zhang, Rujiao Liu, Xiaowei Zhang, Xin Liu, Xiaofeng Wang, Jin Li
• Journal: PloS one (PLoS One) Vol. 9 Issue 1 Pg. e85116 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24416349 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Butadienes
• CCND1 protein, human
• Flavonoids
• Heterocyclic Compounds, 3-Ring
• MAP1LC3B protein, human
• MK 2206
• Membrane Proteins
• Microtubule-Associated Proteins
• Nitriles
• U 0126
• Cyclin D1
• 3-methyladenine
• Chloroquine
• Everolimus
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• Adenine
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• Sirolimus

Topics

• Adenine (analogs & derivatives, pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Apoptosis Regulatory Proteins (antagonists & inhibitors, genetics, metabolism)
• Autophagy (drug effects)
• Beclin-1
• Butadienes (pharmacology)
• Cell Line, Tumor
• Chloroquine (pharmacology)
• Cyclin D1 (antagonists & inhibitors, genetics, metabolism)
• Drug Synergism
• Everolimus
• Flavonoids (pharmacology)
• Gastric Mucosa (drug effects, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Microtubule-Associated Proteins (antagonists & inhibitors, genetics, metabolism)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Nitriles (pharmacology)
• PTEN Phosphohydrolase (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Sirolimus (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)