Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma
Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-formin...
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doaj-40c6dd0f15d84c88a525fbf8aed815b62020-11-25T01:23:30ZengMDPI AGCancers2072-66942019-09-01119131010.3390/cancers11091310cancers11091310Repurposing Penfluridol in Combination with Temozolomide for the Treatment of GlioblastomaHyungsin Kim0Kyuha Chong1Byung-Kyu Ryu2Kyung-Jae Park3Mi OK Yu4Jihye Lee5Seok Chung6Seongkyun Choi7Myung-Jin Park8Yong-Gu Chung9Shin-Hyuk Kang10Department of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Seoul 02842, KoreaDepartment of Neurosurgery, Korea University Guro Hospital, Korea University Medicine, Seoul 08308, KoreaDepartment of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Seoul 02842, KoreaDepartment of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Seoul 02842, KoreaDepartment of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Seoul 02842, KoreaDepartment of Neurosurgery, VHS Medical Center, Seoul 05368, KoreaSchool of Mechanical Engineering, Korea University, Seoul 02841, KoreaSchool of Mechanical Engineering, Korea University, Seoul 02841, KoreaDivisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul 01812, KoreaDepartment of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Seoul 02842, KoreaDepartment of Neurosurgery, Korea University Anam Hospital, Korea University Medicine, Seoul 02842, KoreaDespite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- and dose-dependent manner. At IC50, spheroid size and second-generation spheroid formation were significantly suppressed. Stemness factors, SOX2 and OCT4, were decreased. PFD treatment reduced cancer cell migration and invasion by reducing the Integrin α6 and uPAR levels and suppression of the expression of epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1. GLI1 was found to be involved in PFD-induced EMT inhibition. Furthermore, combinatorial treatment of PFD with temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo. Immunostaining revealed decreased expression of GLI1, SOX2, and vimentin in the PFD treatment group but not in the TMZ-only treatment group. Therefore, PFD can be effectively repurposed for the treatment of glioblastoma by combining it with TMZ.https://www.mdpi.com/2072-6694/11/9/1310penfluridolsphere forming celltumor growthtemozolomideglioblastoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hyungsin Kim Kyuha Chong Byung-Kyu Ryu Kyung-Jae Park Mi OK Yu Jihye Lee Seok Chung Seongkyun Choi Myung-Jin Park Yong-Gu Chung Shin-Hyuk Kang |
spellingShingle |
Hyungsin Kim Kyuha Chong Byung-Kyu Ryu Kyung-Jae Park Mi OK Yu Jihye Lee Seok Chung Seongkyun Choi Myung-Jin Park Yong-Gu Chung Shin-Hyuk Kang Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma Cancers penfluridol sphere forming cell tumor growth temozolomide glioblastoma |
author_facet |
Hyungsin Kim Kyuha Chong Byung-Kyu Ryu Kyung-Jae Park Mi OK Yu Jihye Lee Seok Chung Seongkyun Choi Myung-Jin Park Yong-Gu Chung Shin-Hyuk Kang |
author_sort |
Hyungsin Kim |
title |
Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma |
title_short |
Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma |
title_full |
Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma |
title_fullStr |
Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma |
title_full_unstemmed |
Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma |
title_sort |
repurposing penfluridol in combination with temozolomide for the treatment of glioblastoma |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2019-09-01 |
description |
Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- and dose-dependent manner. At IC50, spheroid size and second-generation spheroid formation were significantly suppressed. Stemness factors, SOX2 and OCT4, were decreased. PFD treatment reduced cancer cell migration and invasion by reducing the Integrin α6 and uPAR levels and suppression of the expression of epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1. GLI1 was found to be involved in PFD-induced EMT inhibition. Furthermore, combinatorial treatment of PFD with temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo. Immunostaining revealed decreased expression of GLI1, SOX2, and vimentin in the PFD treatment group but not in the TMZ-only treatment group. Therefore, PFD can be effectively repurposed for the treatment of glioblastoma by combining it with TMZ. |
topic |
penfluridol sphere forming cell tumor growth temozolomide glioblastoma |
url |
https://www.mdpi.com/2072-6694/11/9/1310 |
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