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

Authors
 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 
Citation
 Oncotarget, Vol.7(40) : 65643-65659, 2016 
Journal Title
 Oncotarget 
Issue Date
2016
MeSH
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
Keywords
HL156A ; biguanide ; glioblastoma ; invasion ; tumorsphere
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.
Files in This Item:
T201604192.pdf Download
DOI
10.18632/oncotarget.11595
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
강석구(Kang, Seok Gu) ORCID logo https://orcid.org/0000-0001-5676-2037
김선호(Kim, Sun Ho) ORCID logo https://orcid.org/0000-0003-0970-3848
김세훈(Kim, Se Hoon) ORCID logo https://orcid.org/0000-0001-7516-7372
김의현(Kim, Eui Hyun) ORCID logo https://orcid.org/0000-0002-2523-7122
육종인(Yook, Jong In) ORCID logo https://orcid.org/0000-0002-7318-6112
윤미진(Yun, Mi Jin) ORCID logo https://orcid.org/0000-0002-1712-163X
이지현(Lee, Ji Hyun) ORCID logo https://orcid.org/0000-0002-9223-9478
장종희(Chang, Jong Hee)
전정용(Jeon, Jeong Yong)
정재호(Cheong, Jae Ho) ORCID logo https://orcid.org/0000-0002-1703-1781
허용민(Huh, Yong Min) ORCID logo https://orcid.org/0000-0002-9831-4475
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/152309
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