title: Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma.
abstract: Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERβ, a second receptor for estrogen, targeting ERβ with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERβ agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERβ agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM.
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Gangadhara R
authors.initials: GR
authors.lastname: Sareddy
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Li
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Jinyou
authors.initials: J
authors.lastname: Liu
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Suryavathi
authors.initials: S
authors.lastname: Viswanadhapalli
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Garcia
authors.affiliation: Cancer Therapy &Research Center, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gruslova
authors.affiliation: Cancer Therapy &Research Center, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cavazos
authors.affiliation: Cancer Therapy &Research Center, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Garcia
authors.affiliation: University of Houston, Houston, TX 77004, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Strom
authors.affiliation: University of Houston, Houston, TX 77004, USA.
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Rajeshwar Rao
authors.initials: RR
authors.lastname: Tekmal
authors.affiliation: Cancer Therapy &Research Center, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.|Hematology &Oncology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Brenner
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.|Cancer Therapy &Research Center, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D047629:Estrogen Receptor beta; D019253:Proto-Oncogene Proteins c-bcl-2; C000592024:erteberel; D003606:Dacarbazine; D053148:Caspase 3; D002945:Cisplatin; D000077204:Temozolomide