MHY218-induced apoptotic cell death is enhanced by the inhibition of autophagy in AGS human gastric cancer cells.

Abstract

We previously reported the anticancer effects of MHY218, which is a hydroxamic acid derivative, in HCT116 human colon cancer cells. In the present study, the involvement of autophagy in the MHY218-induced apoptotic cell death of AGS human gastric cancer cells was investigated. MHY218 treatment induced growth inhibition and apoptotic cell death in a concentration- and time-dependent manner. The induction of apoptosis was confirmed by observations of decreased viability, DNA fragmentation, and an increase in late apoptosis and sub-G1 DNA, which were detected with a flow cytometric analysis. Western blot analyses showed that MHY218 treatment resulted in decreased protein levels of procaspase-8, -9, and -3; cleavage of poly(ADP-ribose) polymerase (PARP); and alterations in the ratio of Bax/Bcl-2 protein expression. Apoptosis induced by MHY218 was involved in the activation of caspase-8, -9, and -3, and it was blocked by the addition of Z-VAD‑FMK, a pan-caspase inhibitor. In addition, autophagy-inducing effects of MHY218 were indicated by cytoplasmic vacuolation, the accumulation of acidic vesicular organelles, the appearance of green fluorescent protein-light-chain 3 (LC3) punctate dots, and increased levels of Beclin-1 and LC3-II protein expression. Pretreatment with the autophagy inhibitors LY294002, 3-methyladenine, chloroquine, and bafilomycin A1 enhanced the induction of apoptosis by MHY218, and this was accompanied by an increase in PARP cleavage. Taken together, these results provide new insights into the role of MHY218 as a potential antitumor agent. The combination of MHY218 with an autophagy inhibitor might be a useful candidate for the chemoprevention and/or treatment of gastric cancer.

• Authors: Pyoung Rak Choi, Yong Jung Kang, Bokyung Sung, Jae Hyun Kim, Hyung Ryong Moon, Hae Young Chung, Sung Eun Kim, Moo In Park, Seun Ja Park, Nam Deuk Kim
• Journal: International journal of oncology (Int J Oncol) Vol. 47 Issue 2 Pg. 563-72 (Aug 2015) ISSN: 1791-2423 [Electronic] Greece
• PMID: 26043797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chromones
• Morpholines
• N1-hydroxy-N8-(4-phenoxyphenyl)octanediamide
• Phenyl Ethers
• Pimelic Acids
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromones (pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• Humans
• Morpholines (pharmacology)
• Phenyl Ethers (pharmacology)
• Pimelic Acids (pharmacology)
• Stomach Neoplasms (drug therapy, metabolism)