Combination Therapy with a PI3K/mTOR Dual Inhibitor and Chloroquine Enhances Synergistic Apoptotic Cell Death in Epstein–Barr Virus-Infected Gastric Cancer Cells
Mi-Young Kim1,2,*, Annie J. Kruger2,3, Ju-Yeon Jeong4, Jaehee Kim4, Phil kyung Shin4, Sun Young Kim5, Joo Young Cho1, Ki Baik Hahm1, and Sung Pyo Hong1
1Digestive Disease Center, 4Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea, 2Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA, 3Division of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC 20007, USA, 5Department of Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
Received September 22, 2018; Revised March 26, 2019; Accepted March 27, 2019.; Published online May 3, 2019.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

ABSTRACT
The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is a promising target for gastric cancer (GC) treatment; however the efficacy of PI3K/mTOR dual inhibitors in GC has not yet been maximized. Additionally, the effect of autophagy regulation by PI3K/mTOR dual inhibitors has not been clearly elucidated in GC treatment. We aimed to show that our newly developed PI3K/mTOR dual inhibitor, CMG002, when combined with an autophagy inhibitor, chloroquine (CQ), potently induces effective cancer cell death in Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) cells, where both the PI3K/AKT/mTOR and autophagy pathways play important roles in disease pathogenesis. EBV- and mockinfected AGS and NUGC3 GC cell lines were treated with CMG002 +/– CQ. PI3K/AKT/mTOR signaling pathway mediators, cellular apoptosis and autophagy markers were confirmed by Western blot assay. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. CMG002 effectively blocked the PI3K/AKT/mTOR pathway by markedly decreasing phosphorylation of AKT and its downstream mediator S6. CMG002 induced G0/G1 cell cycle arrest and enhanced apoptotic cell death in AGS and NUGC3 cells, particularly EBV-infected cells compared with mockinfected cells, as confirmed by flow cytometric analyses and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays. The combination of CMG002 plus CQ synergistically increased apoptotic cell death in EBV-infected GC cell lines when compared with CMG002 alone ( P < 0.05). Our results suggest that the new PI3K/mTOR dual inhibitor, CMG002, when used in combination with the autophagy inhibitor, CQ, provides enhanced therapeutic efficacy against EBVaGC.
Keywords: apoptosis, autophagy, chloroquine, gastric cancer, PI3K/mTOR dual inhibitor
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31 May 2019 Volume 42,
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