Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A)
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Junjeong Choi1,2,*, Ji-Hyun Lee3,*, Ilkyoo Koh4,*, Jin-Kyoung Shim3, Junseong Park3, Jeong Yong Jeon5, Mijin Yun5, Se Hoon Kim6, Jong In Yook7, Eui Hyun Kim3, Jong Hee Chang3, Sun Ho Kim3, Yong Min Huh8, Su Jae Lee9, Michael Pollak10, Pilnam Kim4, Seok-Gu Kang3, Jae-Ho Cheong11
1Department of Pharmacy, College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
2Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea
3Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
4Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
5Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
6Departments of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
7Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea
8Departments of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
9Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
10Department of Oncology and Medicine, McGill University, Gerald Bronfman Centre, Montreal, Quebec, Canada
11Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
*These authors have contributed equally to this work
Pilnam Kim, email: firstname.lastname@example.org
Seok-Gu Kang, email: email@example.com
Keywords: biguanide, glioblastoma, HL156A, invasion, tumorsphere
Received: January 26, 2016 Accepted: August 13, 2016 Published: August 25, 2016
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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