title: A new oridonin analog suppresses triple-negative breast cancer cells and tumor growth via the induction of death receptor 5.
abstract: Triple-negative breast cancer (TNBC) remains the leading cause of death among women with breast cancer worldwide. Oridonin is a natural anti-cancer compound that is isolated from the traditional Chinese herb Rabdosia rubescens. However, the antitumor efficacies of oridonin in the treatments of TNBC and other cancers are far from ideal. In this study, we investigated a series of newly designed oridonin analogs in terms of their actions against HCC1806 and HCC1937 TNBC cell lines and identified CYD-6-28, which significantly inhibits cancer cell proliferation and induces G2/M-phase cell cycle arrest and apoptosis. CYD-6-28 induces the expression of p21 and the cleavage of caspase-3, -7, -8 and PARP and inhibits the expression levels of Cyclin D1, FLIPL and XIAP. CYD-6-28 also inhibits the activations of STAT3 and AKT and induces the activation of ERK. We demonstrated that CYD-6-28 induces apoptosis at least partially by inducing the expression of death receptor 5 (DR5). Finally, CYD-6-28 significantly suppresses HCC1806 xenograft tumor growth in nude mice at 5 mg/kg without affecting body weight. Taken together, these results indicate that CYD-6-28 has the potential to be developed as a therapeutic agent to treat TNBC.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China; Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming, Yunnan 650500, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
authors.forename: Chuan-Huizhi
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Ding
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: jizhou@utmb.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. Electronic address: chenc@mail.kiz.ac.cn.
authors.forename: Ceshi
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C000621543:CYD-6-28; D018797:Cell Cycle Proteins; D045786:Diterpenes, Kaurane; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C505639:TNFRSF10B protein, human; C011959:oridonin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Apoptosis; Death receptor 5 (DR5); Oridonin analog; Therapy; Triple-negative breast cancer