title: Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A).
abstract: Studies have investigated biguanide-derived agents for the treatment of cancers and have reported their effects against tumorspheres (TSs). The purpose of this study was determining the effects of HL156A, a newly designed biguanide with improved pharmacokinetics, on glioblastoma TSs (GMB TSs) and assess the feasibility of this drug as a new line of therapy against glioblastoma, alone or combined with a conventional therapeutic agent, temozolomide(TMZ). The effects of HL156A, alone and combined with TMZ, on the stemness and invasive properties of GBM TSs and survival of orthotopic xenograft animals were assessed. HL156A, combined with TMZ, inhibited the stemness of GBM TSs, proven by neurosphere formation assay and marker expression. Three-dimensional collagen matrix invasion assays provided evidence that combined treatment inhibited invasive properties, compared with control and TMZ-alone treatment groups. TMZ alone and combined treatment repressed the expression of epithelial-mesenchymal transition-related genes. A gene ontology comparison of TMZ and combination-treatment groups revealed altered expression of genes encoding proteins involved in cellular adhesion and migration. Combined treatment with HL156A and TMZ showed survival benefits in an orthotopic xenograft mouse model. The inhibitory effect of combination treatment on the stemness and invasive properties of GBM TSs suggest the potential usage of this regimen as a novel strategy for the treatment of GBM.
authors: Department of Pharmacy, College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
authors: Junjeong
authors: J
authors: Choi
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Ji-Hyun
authors: JH
authors: Lee
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Ilkyoo
authors: I
authors: Koh
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jin-Kyoung
authors: JK
authors: Shim
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Junseong
authors: J
authors: Park
authors: Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jeong Yong
authors: JY
authors: Jeon
authors: Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Mijin
authors: M
authors: Yun
authors: Departments of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Se Hoon
authors: SH
authors: Kim
authors: Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors: Jong In
authors: JI
authors: Yook
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Eui Hyun
authors: EH
authors: Kim
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jong Hee
authors: JH
authors: Chang
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Sun Ho
authors: SH
authors: Kim
authors: Departments of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Yong Min
authors: YM
authors: Huh
authors: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea.
authors: Su Jae
authors: SJ
authors: Lee
authors: Department of Oncology and Medicine, McGill University, Gerald Bronfman Centre, Montreal, Quebec, Canada.
authors: Michael
authors: M
authors: Pollak
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Pilnam
authors: P
authors: Kim
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Seok-Gu
authors: SG
authors: Kang
authors: Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jae-Ho
authors: JH
authors: Cheong
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004359:Drug Therapy, Combination; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D011759:Pyrrolidines / Q000494:pharmacology*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006146:Guanidines; C000609148:HL156A; D011759:Pyrrolidines; D003606:Dacarbazine; D000077204:Temozolomide
keywords: HL156A; biguanide; glioblastoma; invasion; tumorsphere