title: Em08red, a dual functional antiproliferative emodin analogue, is a downregulator of ErbB2 expression and inducer of intracellular oxidative stress.
abstract: Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death.
authors: Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung, Taiwan.
authors: Fong-Pin
authors: FP
authors: Liang
authors: Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung, Taiwan.
authors: Jin-Cherng
authors: JC
authors: Lien
authors: School of Pharmacy and Department of Pediatrics, Children's Hospital, China Medical University Hospital, Taichung, Taiwan.
authors: Yu-Hua
authors: YH
authors: Wu
authors: School of Pharmacy and Department of Pediatrics, Children's Hospital, China Medical University Hospital, Taichung, Taiwan.
authors: Chien-Shu
authors: CS
authors: Chen
authors: Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung, Taiwan ; School of Pharmacy and Department of Pediatrics, Children's Hospital, China Medical University Hospital, Taichung, Taiwan ; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors: Shin-Hun
authors: SH
authors: Juang
mesh_terms: D000875:Anthralin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000875:Anthralin; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: ErbB2; em08red; emodin; reactive oxygen species; structure-activity relationship