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Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A)

 Junjeong Choi  ;  Ji-Hyun Lee  ;  Ilkyoo Koh  ;  Jin-Kyoung Shim  ;  Junseong Park  ;  Jeong Yong Jeon  ;  Mijin Yun  ;  Se Hoon Kim  ;  Jong In Yook  ;  Eui Hyun Kim  ;  Jong Hee Chang  ;  Sun Ho Kim  ;  Yong Min Huh  ;  Su Jae Lee  ;  Michael Pollak  ;  Pilnam Kim  ;  Seok-Gu Kang  ;  Jae-Ho Cheong 
 ONCOTARGET , Vol.7(40) : 65643-65659, 2016 
Journal Title
Issue Date
Animals ; Antineoplastic Agents, Alkylating/pharmacology* ; Apoptosis/drug effects ; Brain Neoplasms/drug therapy ; Brain Neoplasms/pathology* ; Cell Proliferation/drug effects ; Dacarbazine/analogs & derivatives* ; Dacarbazine/pharmacology ; Drug Therapy, Combination ; Epithelial-Mesenchymal Transition/drug effects ; Gene Expression Regulation, Neoplastic/drug effects* ; Glioblastoma/drug therapy ; Glioblastoma/pathology* ; Guanidines/pharmacology* ; Humans ; Male ; Mice ; Mice, Inbred ICR ; Mice, Nude ; Neoplasm Invasiveness ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/pathology* ; Pyrrolidines/pharmacology* ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
HL156A ; biguanide ; glioblastoma ; invasion ; tumorsphere
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.
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1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Sun Ho(김선호) ORCID logo https://orcid.org/0000-0003-0970-3848
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Kim, Eui Hyun(김의현) ORCID logo https://orcid.org/0000-0002-2523-7122
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Ji Hyun(이지현) ORCID logo https://orcid.org/0000-0002-9223-9478
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
Jeon, Jeong Yong(전정용)
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
Huh, Yong Min(허용민) ORCID logo https://orcid.org/0000-0002-9831-4475
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