CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS
Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) play essential roles in promoting cholangiocarcinoma (CCA) cell survival by mediating paracrine crosstalk between tumor and cancer-associated fibroblasts (CAFs), indicating the potential of PDGFR as a target for CCA treatment. Clini...
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| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/17/1/9 |
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| author | Jinchutha Duangdara Boonyakorn Boonsri Apinya Sayinta Kittiya Supradit Pakpoom Thintharua Supeecha Kumkate Chinnawut Suriyonplengsaeng Noppadol Larbcharoensub Somkit Mingphruedhi Narongsak Rungsakulkij Paramin Muangkaew Pongsatorn Tangtawee Watoo Vassanasiri Wikran Suragul Tavan Janvilisri Rutaiwan Tohtong David O. Bates Kanokpan Wongprasert |
| author_facet | Jinchutha Duangdara Boonyakorn Boonsri Apinya Sayinta Kittiya Supradit Pakpoom Thintharua Supeecha Kumkate Chinnawut Suriyonplengsaeng Noppadol Larbcharoensub Somkit Mingphruedhi Narongsak Rungsakulkij Paramin Muangkaew Pongsatorn Tangtawee Watoo Vassanasiri Wikran Suragul Tavan Janvilisri Rutaiwan Tohtong David O. Bates Kanokpan Wongprasert |
| author_sort | Jinchutha Duangdara |
| collection | DOAJ |
| description | Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) play essential roles in promoting cholangiocarcinoma (CCA) cell survival by mediating paracrine crosstalk between tumor and cancer-associated fibroblasts (CAFs), indicating the potential of PDGFR as a target for CCA treatment. Clinical trials evaluating PDGFR inhibitors for CCA treatment have shown limited efficacy. Furthermore, little is known about the role of PDGF/PDGFR expression and the mechanism underlying PDGFR inhibitors in CCA related to <i>Opisthorchis viverrini</i> (OV). Therefore, we examined the effect of PDGFR inhibitors in OV-related CCA cells and investigated the molecular mechanism involved. We found that the PDGF and PDGFR mRNAs were overexpressed in CCA tissues compared to resection margins. Notably, PDGFR-α showed high expression in CCA cells, while PDGFR-β was predominantly expressed in CAFs. The selective inhibitor CP-673451 induced CCA cell death by suppressing the PI3K/Akt/Nrf2 pathway, leading to a decreased expression of Nrf2-targeted antioxidant genes. Consequently, this led to an increase in ROS levels and the promotion of CCA apoptosis. CP-673451 is a promising PDGFR-targeted drug for CCA and supports the further clinical investigation of CP-673451 for CCA treatment, particularly in the context of OV-related cases. |
| first_indexed | 2024-03-08T10:38:48Z |
| format | Article |
| id | doaj.art-cb30564eb065479f9a10b008793cc418 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-08T10:38:48Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-cb30564eb065479f9a10b008793cc4182024-01-26T18:04:32ZengMDPI AGPharmaceuticals1424-82472023-12-01171910.3390/ph17010009CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROSJinchutha Duangdara0Boonyakorn Boonsri1Apinya Sayinta2Kittiya Supradit3Pakpoom Thintharua4Supeecha Kumkate5Chinnawut Suriyonplengsaeng6Noppadol Larbcharoensub7Somkit Mingphruedhi8Narongsak Rungsakulkij9Paramin Muangkaew10Pongsatorn Tangtawee11Watoo Vassanasiri12Wikran Suragul13Tavan Janvilisri14Rutaiwan Tohtong15David O. Bates16Kanokpan Wongprasert17Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Biology, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandDepartment of Surgery, Hepato-Pancreato-Biliary Division, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandDepartment of Surgery, Hepato-Pancreato-Biliary Division, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandDepartment of Surgery, Hepato-Pancreato-Biliary Division, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandDepartment of Surgery, Hepato-Pancreato-Biliary Division, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandDepartment of Surgery, Hepato-Pancreato-Biliary Division, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandDepartment of Surgery, Hepato-Pancreato-Biliary Division, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandGraduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, ThailandDepartment of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, ThailandCentre for Cancer Sciences, Division of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UKDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, ThailandPlatelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) play essential roles in promoting cholangiocarcinoma (CCA) cell survival by mediating paracrine crosstalk between tumor and cancer-associated fibroblasts (CAFs), indicating the potential of PDGFR as a target for CCA treatment. Clinical trials evaluating PDGFR inhibitors for CCA treatment have shown limited efficacy. Furthermore, little is known about the role of PDGF/PDGFR expression and the mechanism underlying PDGFR inhibitors in CCA related to <i>Opisthorchis viverrini</i> (OV). Therefore, we examined the effect of PDGFR inhibitors in OV-related CCA cells and investigated the molecular mechanism involved. We found that the PDGF and PDGFR mRNAs were overexpressed in CCA tissues compared to resection margins. Notably, PDGFR-α showed high expression in CCA cells, while PDGFR-β was predominantly expressed in CAFs. The selective inhibitor CP-673451 induced CCA cell death by suppressing the PI3K/Akt/Nrf2 pathway, leading to a decreased expression of Nrf2-targeted antioxidant genes. Consequently, this led to an increase in ROS levels and the promotion of CCA apoptosis. CP-673451 is a promising PDGFR-targeted drug for CCA and supports the further clinical investigation of CP-673451 for CCA treatment, particularly in the context of OV-related cases.https://www.mdpi.com/1424-8247/17/1/9cholangiocarcinoma<i>Opisthorchis viverrini</i>CP-673451PDGFR inhibitorNrf2 |
| spellingShingle | Jinchutha Duangdara Boonyakorn Boonsri Apinya Sayinta Kittiya Supradit Pakpoom Thintharua Supeecha Kumkate Chinnawut Suriyonplengsaeng Noppadol Larbcharoensub Somkit Mingphruedhi Narongsak Rungsakulkij Paramin Muangkaew Pongsatorn Tangtawee Watoo Vassanasiri Wikran Suragul Tavan Janvilisri Rutaiwan Tohtong David O. Bates Kanokpan Wongprasert CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS Pharmaceuticals cholangiocarcinoma <i>Opisthorchis viverrini</i> CP-673451 PDGFR inhibitor Nrf2 |
| title | CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS |
| title_full | CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS |
| title_fullStr | CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS |
| title_full_unstemmed | CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS |
| title_short | CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in <i>Opisthorchis viverrini</i>-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS |
| title_sort | cp 673451 a selective platelet derived growth factor receptor tyrosine kinase inhibitor induces apoptosis in i opisthorchis viverrini i associated cholangiocarcinoma via nrf2 suppression and enhanced ros |
| topic | cholangiocarcinoma <i>Opisthorchis viverrini</i> CP-673451 PDGFR inhibitor Nrf2 |
| url | https://www.mdpi.com/1424-8247/17/1/9 |
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