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

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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.

Original languageEnglish
Pages (from-to)65643-65659
Number of pages17
JournalOncotarget
Volume7
Issue number40
DOIs
Publication statusPublished - 2016 Jan 1

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All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Choi, J., Lee, J. H., Koh, I., Shim, J. K., Park, J., Jeon, J. Y., Yun, M., Kim, S. H., Yook, J. I., Kim, E. H., Chang, J. H., Kim, S. H., Huh, Y. M., Lee, S. J., Pollak, M., Kim, P., Kang, S. G., & Cheong, J. H. (2016). Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A). Oncotarget, 7(40), 65643-65659. https://doi.org/10.18632/oncotarget.11595