title: KML001, a telomere-targeting drug, sensitizes glioblastoma cells to temozolomide chemotherapy and radiotherapy through DNA damage and apoptosis.
abstract: Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects on in vitro survival of glioblastoma cells, cell death by in vitro temozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylated γ-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma.
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Cancer Stem Cell Research Center, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Seon Rang
authors.identifier: 0000-0003-2640-5025
authors.initials: SR
authors.lastname: Woo
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Cancer Stem Cell Research Center, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Ham
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Wonyoung
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Heekyoung
authors.identifier: 0000-0002-3854-5458
authors.initials: H
authors.lastname: Yang
authors.affiliation: Pharmaceutical Division, Komipharm International Co., Ltd., Seoul 429-450, Republic of Korea ; Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Sujong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Juyoun
authors.initials: J
authors.lastname: Jin
authors.affiliation: Cancer Stem Cell Research Center, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Department of Anatomy and Cell Biology, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Center for Molecular Medicine, Samsung Biomedical Research Institute, Seoul 135-710, Republic of Korea.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Cancer Stem Cell Research Center, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea ; Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000008:administration & dosage*; D004249:DNA Damage / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D017670:Sodium Compounds / Q000008:administration & dosage*; D016615:Telomere / Q000187:drug effects* / Q000235:genetics; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018053:Arsenites; D011838:Radiation-Sensitizing Agents; D017670:Sodium Compounds; C017947:sodium arsenite; D003606:Dacarbazine; D000077204:Temozolomide