title: Novel sesquiterpene lactone analogues as potent anti-breast cancer agents.
abstract: Triple-negative breast cancer (TNBC) is associated with high grade, metastatic phenotype, younger patient age, and poor prognosis. The discovery of an effective anti-TNBC agent has been a challenge in oncology. In this study, fifty-eight ester derivatives (DETDs) with a novel sesquiterpene dilactone skeleton were organically synthesized from a bioactive natural product deoxyelephantopin (DET). Among them, DETD-35 showed potent antiproliferative activities against a panel of breast cancer cell lines including TNBC cell line MDA-MB-231, without inhibiting normal mammary cells M10. DETD-35 exhibited a better effect than parental DET on inhibiting migration, invasion, and motility of MDA-MB-231 cells in a concentration-dependent manner. Comparative study of DETD-35, DET and chemotherapeutic drug paclitaxel (PTX) showed that PTX mainly caused a typical time-dependent G2/M cell-cycle arrest, while DETD-35 or DET treatment induced cell apoptosis. In vivo efficacy of DETD-35 was evaluated using a lung metastatic MDA-MB-231 xenograft mouse model. DETD-35 significantly suppressed metastatic pulmonary foci information along with the expression level of VEGF and COX-2 in SCID mice. DETD-35 also showed a synergistic antitumor effect with PTX in vitro and in vivo. This study suggests that the novel compound DETD-35 may have a potential to be further developed into a therapeutic or adjuvant agent for chemotherapy against metastatic TNBC.
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA. Electronic address: kngoto@p.kanazawa-u.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University 11031, Taipei, Taiwan, ROC.
authors.forename: Jo-Yu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan, ROC; Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan, ROC.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Cheng
authors.affiliation: School of Science, Monash University Sunway Campus, Selangor 47500, Malaysia.
authors.forename: Wai-Leng
authors.initials: WL
authors.lastname: Lee
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Munehisa
authors.initials: M
authors.lastname: Takeya
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, 2 Yuh-Der Road, Taichung 40447, Taiwan, ROC. Electronic address: khlee@ncu.edu.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University 11031, Taipei, Taiwan, ROC; Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan, ROC; Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC. Electronic address: lfshyur@ccvax.sinica.edu.tw.
authors.forename: Lie-Fen
authors.initials: LF
authors.lastname: Shyur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000187:drug effects* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D012717:Sesquiterpenes; C528427:deoxyelephantopin
keywords: DET derivatives; Deoxyelephantopin; Lung metastasis; Paclitaxel; Triple-negative breast cancer