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. Clin Cancer Res; 20(16); 4302-13. Ó2014 AACR.

The chalcone derivative HymnPro generates reactive oxygen species through depletion of intracellular glutathione

“…3E). Our previous study has demonstrated that DPP-23 induces ROS production and triggers apoptosis through the unfolded protein response (UPR) in the ER (Shin et al 2014). Thus, it seems likely that HymnPro might stimulate ER stress-mediated apoptosis due to ROS accumulation in a manner similar to that of DPP-23.…”

“…Capan-1 cells were treated with 20 lM HymnPro for 24 or 48 h. Cellular DNA contents and propidium iodide (PI)-stained dead cells were analyzed by flow cytometry as previously described (Shin et al 2014). Fluorescence was measured with a FACSCalibur flow cytometer (BectonDickinson Immunocytometry Systems, San Jose, CA, USA).…”

“…Briefly, total cell lysates were prepared, and cellular GSH contents were analyzed by measuring the concentrations of yellow-colored 5-thio-2-nitrobenzoic acid, a product of the glutathione-catalyzed reduction of 5,5 0 -dithiobis-2-nitrobenzoic acid, with a UV spectrometer at 405 nm, as described previously (Shin et al 2014).…”

“…The fluorescence intensity was then analyzed using a FACSCalibur flow cytometer as described previously (Shin et al 2014). …”

“…1A), inhibits microtubule polymerization through tubulin binding, thereby disrupting microtubule dynamics during mitosis (Shin et al 2013). We also have reported that the novel methoxychalcone derivative, 2 0 ,3,5-trimethoxychalcone (named DPP-23), promotes reactive oxygen species (ROS) production and triggers endoplasmic reticulum (ER) stress-mediated apoptosis (Shin et al 2014). In a previous study, it was demonstrated that piperlongumine, a natural anti-cancer product (Raj et al 2011), contains multiple Michael acceptor sites, including C2-C3 and C7-C8 olefins, which play a determining role in the molecule's cytotoxic mechanism by depleting intracellular glutathione (GSH) and consequently elevating ROS levels (Adams et al 2012).…”