title: Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis.
abstract: Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated.
  
  
  
  Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively.
  
  
  
  Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells.
  
  
  
  To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status. Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects.
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran, Iran. Electronic address: bhr.bigdeli@ut.ac.ir.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Bigdeli
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran, Iran. Electronic address: goliaei@ut.ac.ir.
authors.forename: Bahram
authors.initials: B
authors.lastname: Goliaei
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran, Iran. Electronic address: n.masoudi@alumni.ut.ac.ir.
authors.forename: Nastaran
authors.initials: N
authors.lastname: Masoudi-Khoram
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran, Iran. Electronic address: n.jooyan@ut.ac.ir.
authors.forename: Najmeh
authors.initials: N
authors.lastname: Jooyan
authors.affiliation: Department of Radiotherapy, Iran University of Medical Sciences (IUMS), Shahid Hemmat Highway, Tehran, Iran. Electronic address: nikoofar@iums.ac.ir.
authors.forename: Alireza
authors.initials: A
authors.lastname: Nikoofar
authors.affiliation: Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Prof. Yousef Sobouti Blvd., Gava Zang, Zanjan, Iran. Electronic address: rouhani@iasbs.ac.ir.
authors.forename: Maryam
authors.initials: M
authors.lastname: Rouhani
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Daneshjo St., Evin, Tehran, Iran. Electronic address: Haghparast@sbmu.ac.ir.
authors.forename: Abbas
authors.initials: A
authors.lastname: Haghparast
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran, Iran. Electronic address: mamashli@ut.ac.ir.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Mamashli
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D004260:DNA Repair; D005260:Female; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D017705:Lignans; D011838:Radiation-Sensitizing Agents; D015107:4-Butyrolactone; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone
keywords: Breast cancer; Chromosomal aberrations; DNA repair; Enterolactone; Micronuclei; Radiosensitizer