title: Ovatodiolide sensitizes aggressive breast cancer cells to doxorubicin, eliminates their cancer stem cell-like phenotype, and reduces doxorubicin-associated toxicity.
abstract: Triple-negative breast cancer (TNBC) is chemotherapy-refractory and associated with poor clinical prognosis. Doxorubicin (Doxo), a class I anthracycline and first-line anticancer agent, effective against a wide spectrum of neoplasms including breast carcinoma, is associated with several cumulative dose-dependent adverse effects, including cardiomyopathy, typhilitis, and acute myelotoxicity. This study evaluated the usability of Ovatodiolide (Ova) in sensitizing TNBC cells to Doxo cytotoxicity, so as to reduce Doxo effective dose and consequently its adverse effects. TNBC cell lines MDA-MB-231 and HS578T were used. Pre-treatment of the TNBC cells with 10 µM Ova 24 h before Doxo administration increased the Doxo anticancer effect (IC50 1.4 µM) compared to simultaneous treatment with Doxo ( IC50 1.8 µM), or Doxo alone (IC50 9.2 µM). Intracellular accumulation of Doxo was lowest in Ova pre-treated cells at all Doxo concentrations, when compared with Doxo or simultaneously treated cells. In comparison to the Doxo-only group, cell cycle analysis of MDA-MB-231 cells treated concurrently with 2.5 µM Ova and 1.25 µM Doxo showed increased percentage of cells arrested at G0/G1; however, pre-treatment with the same concentration of Ova 24 h before Doxo showed greater tumor growth inhibition, with a 2.4-fold increased percentage of cells in G0/G1 arrest, greater Doxo-induced apoptosis, and significantly reduced intracellular Doxo accumulation. Additionally, Ova-sensitized TNBC cells also lost their cancer stem cell-like phenotype evidenced by significant dissolution, necrosis of formed mammospheres. Taken together, these findings indicate that Ova sensitizes TNBC cells to Doxo and potentiates doxorubicin-induced elimination of the TNBC cancer stem cell-like phenotype.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan.
authors.forename: Oluwaseun Adebayo
authors.initials: OA
authors.lastname: Bamodu
authors.affiliation: Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.
authors.forename: David T W
authors.initials: DT
authors.lastname: Tzeng
authors.affiliation: Graduate Institute of Translational Medicine, Taipei Medical University, Taipei City, Taiwan; The PhD Program of Translational Medicine, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan.
authors.forename: Liang Shun
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan. Electronic address: ctyeh@s.tmu.edu.tw.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Tri-Service General Hospital, Neihu District, Taipei City, Taiwan. Electronic address: j0607@ms6.hinet.net.
authors.forename: Tsu-Yi
authors.initials: TY
authors.lastname: Chao
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D004224:Diterpenes; C432447:ovatodiolide; D004317:Doxorubicin
keywords: Breast cancer; Cancer stem cell; Doxorubicin; Drug toxicity; Ovatodiolide; TNBC