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         headline:Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA
         description:Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.
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      headline:Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA
      description:Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.
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         Bexarotene
         All-trans retinoic acid
         GBM
         Glioblastoma multiforme
         Transglutaminase 2
         Cancer Research
         Biomedicine
         general
         Oncology
         Hematology
         Surgical Oncology
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            name:Korea Research Institute of Chemical Technology (KRICT)
            address:
               name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
               type:PostalAddress
            type:Organization
      name:Jung-Ok Lee
      affiliation:
            name:Korea Research Institute of Chemical Technology (KRICT)
            address:
               name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
               type:PostalAddress
            type:Organization
      name:Ji-Hwan Park
      affiliation:
            name:POSTECH
            address:
               name:Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
               type:PostalAddress
            type:Organization
      name:Daehee Hwang
      affiliation:
            name:Institute for Basic Science
            address:
               name:Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, Daegu, Republic of Korea
               type:PostalAddress
            type:Organization
            name:POSTECH
            address:
               name:Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
               type:PostalAddress
            type:Organization
      name:Ho Jun Seol
      affiliation:
            name:Sungkyunkwan University School of Medicine
            address:
               name:Department of Neurosurgery, Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
               type:PostalAddress
            type:Organization
      name:Heeyeong Cho
      affiliation:
            name:Korea Research Institute of Chemical Technology (KRICT)
            address:
               name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
               type:PostalAddress
            type:Organization
            name:University of Science and Technology (UST)
            address:
               name:Pharmacology Research Medicinal and Pharmaceutical Chemistry, University of Science and Technology (UST), Daejeon, Republic of Korea
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Pharmacology Research Medicinal and Pharmaceutical Chemistry, University of Science and Technology (UST), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
      name:Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, Daegu, Republic of Korea
      name:Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
      name:Department of Neurosurgery, Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
      name:Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
      name:Pharmacology Research Medicinal and Pharmaceutical Chemistry, University of Science and Technology (UST), Daejeon, Republic of Korea
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