title: A Novel Polyphenol Conjugate Sensitizes Cisplatin-Resistant Head and Neck Cancer Cells to Cisplatin via Nrf2 Inhibition.
abstract: Many cancer cells show acquired resistance to chemotherapeutic agents, such as cisplatin. This is a major cause of cancer treatment failure, and novel agents to overcome resistance are thus urgently required. A novel synthetic polyphenol conjugate, (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23), selectively kills tumor cells via the reactive oxygen species (ROS)-mediated unfolded protein response. We investigated the ability of DPP-23 to overcome cisplatin resistance in head and neck cancer (HNC) cells and further clarified its molecular mechanisms of action. Cisplatin-resistant HNC cell lines and their parental and other HNC cell lines were used. The effects of cisplatin and DPP-23 were assessed alone and in combination in HNC and normal cells using cell viability, cell cycle, and cell death assays, by measuring glutathione (GSH), ROS, and protein levels, and via preclinical mouse studies. DPP-23 induced selective cell death in HNC cells, including cisplatin-resistant HNC cells, but spared normal cells, via cellular GSH depletion and ROS accumulation. The effect was blocked by the antioxidant N-acetyl-L-cysteine. DPP-23 activated p53 and its related cell death pathways via a robust accumulation of cellular ROS that involved inhibition of nuclear factor erythroid 2-related factor 2 antioxidant defense mechanisms. Thus, DPP-23 significantly overcame cisplatin resistance in HNC cells in vitro and in vivo As a promising anticancer strategy, ROS generation and subsequent selective cancer cell killing by DPP-23 might help to overcome cisplatin resistance in HNC. Mol Cancer Ther; 15(11); 2620-9. ©2016 AACR.
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. rohjl@amc.seoul.kr.
authors.forename: Jong-Lyel
authors.initials: JL
authors.lastname: Roh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors*; D059808:Polyphenols / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D059808:Polyphenols; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin