Targeting cancer cells via the reactive oxygen species-mediated unfolded protein response with a novel synthetic polyphenol conjugate.

Abstract

PURPOSE:

The selective killing of tumor cells is an important strategy for cancer therapeutics. The aim of this study was to develop a novel antitumor agent that is safe for normal cells with the ability to selectively target cancer cells.

EXPERIMENTAL DESIGN:

On the basis of quantitative structure-activity relationship, we synthesized a novel polyphenol conjugate (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23). We evaluated the effect of DPP-23 on proliferation, cell cycle, and apoptosis in various tumor cells. We also assessed molecular targets of DPP-23 using genome-wide expression profiling by DNA microarray and real-time PCR array systems.

RESULTS:

DPP-23 effectively inhibited the growth of cancer cells in vitro and in vivo (xenografts in Balb/c nude mice). At a molecular level, DPP-23 targeted the unfolded protein response (UPR) in the endoplasmic reticulum (ER) through the production of reactive oxygen species (ROS) in cancer cells, but not in normal cells, resulting in selective killing of tumor cells via caspase-dependent apoptosis.

CONCLUSIONS:

The selective generation of ROS in cancer cells could be an attractive strategy for the selective killing of cancer cells, while maintaining negligible cytotoxicity to normal cells. DPP-23 represents a promising novel therapeutic agent for the selective production of ROS in cancer cells.

• Authors: Soon Young Shin, Jong Min Lee, Mi So Lee, Dongsoo Koh, Hyeryoung Jung, Yoongho Lim, Young Han Lee
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 16 Pg. 4302-13 (Aug 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24938523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• 3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one
• Antineoplastic Agents
• Chalcones
• Polyphenols
• RNA, Messenger
• Reactive Oxygen Species

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Chalcones (chemical synthesis, pharmacology)
• Endoplasmic Reticulum (drug effects)
• Fluorescent Antibody Technique
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microscopy, Electron, Transmission
• Neoplasms (drug therapy, metabolism, pathology)
• Polyphenols (chemistry, pharmacology)
• RNA, Messenger (genetics)
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Unfolded Protein Response (drug effects)
• Xenograft Model Antitumor Assays