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.
Highlights
The integration of chemotherapy and targeted therapy with radiation has become more popular in many human cancers in the emerging era of personalized therapy [1]
Cell culture and establishment of cisplatin-resistant head and neck cancer (HNC) cells Asan Medical Center (AMC; Seoul, Republic of Korea) cancer cell lines previously established from the primary tumors of head and neck in our institution [24] and other cancer cell lines were obtained from the Korea Cell Line Bank and ATCC
The growth, viability, and colony-forming abilities of both cisplatin-sensitive and -resistant HNC cells were markedly inhibited by treatment with DPP-23 2.5 to 10 mmol/L for 72 hours (Figs. 1C and 2A)
Summary
The integration of chemotherapy and targeted therapy with radiation has become more popular in many human cancers in the emerging era of personalized therapy [1]. Cisplatin is a very old antineoplastic agent first described in 1844 [2], but it is still an important therapeutic tool for various types of human solid neoplasms, including testicular, bladder, ovarian, lung, colorectal, and head and neck cancer As a first-line chemotherapeutic agent, cisplatin is currently used in combination with radiotherapy in the organ preservation protocol for HNC [4]. Cisplatin provokes undesirable moderate-to-severe adverse effects involving the immune system, kidney, gastrointestinal tract, and nervous system [6]. This has prompted the use of other platinum derivatives of oxaliplatin and carboplatin and the continuous development of other novel platinum-containing antineoplastic agents to broaden their clinical use [7].
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