Open AccessSelective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma
Author(s) -
Gangadhara R. Sareddy,
Xiaonan Li,
Jinyou Liu,
Suryavathi Viswanadhapalli,
Lauren Garcia,
Aleksandra Gruslova,
David Cavazos,
M.J. Díaz García,
Anders Ström,
Jan Åke Gustafsson,
Rajeshwar Rao Tekmal,
Andrew Brenner,
Ratna K. Vadlamudi
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep24185
Subject(s) - temozolomide , cancer research , in vivo , agonist , estrogen receptor , glioma , apoptosis , estrogen , pharmacology , medicine , cisplatin , estrogen receptor beta , biology , receptor , cancer , breast cancer , chemotherapy , biochemistry , microbiology and biotechnology
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.