title: A771726, an anti-inflammatory drug, exerts an anticancer effect and reverses tamoxifen resistance in endocrine-resistant breast cancer cells.
abstract: A771726, an orally available anti-inflammatory agent, has been approved for the treatment of multiple sclerosis by diminishing entire inflammatory responses through multiple signaling pathways. Recently, a few emerging studies have focused on the potential application of A771726 in cancer therapy, less on the treatment of breast cancer and particularly on overcoming drug resistance in breast cancer. We report here for the first time the cytotoxic activity and drug resistance reversal of A771726 in acquired tamoxifen-resistant breast cancer cell line MCF-7/LCC9. We discovered that A771726 treatment showed antiproliferative activities in MCF-7/LCC9 cells, which were even more sensitive to A771726 than their parental tamoxifen-sensitive cells (MCF‑7). A771726 also exerted pro-apoptotic activities and induced cell cycle arrest at the G1 phase. Notably, treatment of A771726 restored the sensitivity of MCF-7/LCC9 cells to tamoxifen. Western blot analysis revealed that A771726 decreased the phosphorylation level of Src, one key driver of tamoxifen resistance. Moreover, in order to comprehensively clarify the mechanisms of A771726 in anti-estrogen-resistant cells, we explored a genome-wide transcriptomic analysis, and showed that A771726 could modulate multiple signaling pathways (e.g. cell cycle, apoptosis, MAPK, metabolism and p53 signaling pathway) and cellular processes (e.g. signal transduction, transcription and cell cycle). Overall, our results indicate that A771726 alone and the combination of A771726 with anti-estrogens may be of therapeutic benefit for ER-positive and endocrine-resistant breast cancer.
authors.affiliation: Comprehensive Breast Health Centre, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Ou
authors.initials: O
authors.lastname: Huang
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Zuoquan
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Xiangcheng People's Hospital, Suzhou, Jiangsu 215131, P.R. China.
authors.forename: Weili
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Comprehensive Breast Health Centre, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Comprehensive Breast Health Centre, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
authors.forename: Hongchun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Comprehensive Breast Health Centre, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Kunwei
authors.initials: K
authors.lastname: Shen
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003437:Crotonates; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology*; D061986:MCF-7 Cells; D009570:Nitriles; D010766:Phosphorylation; D013629:Tamoxifen / Q000009:adverse effects; D014052:Toluidines; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000893:Anti-Inflammatory Agents; D003437:Crotonates; D006885:Hydroxybutyrates; D009570:Nitriles; D014052:Toluidines; D013629:Tamoxifen; C527525:teriflunomide; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human