CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS
Issued Date
2024-01-01
Resource Type
eISSN
14248247
Scopus ID
2-s2.0-85183103807
Journal Title
Pharmaceuticals
Volume
17
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Pharmaceuticals Vol.17 No.1 (2024)
Suggested Citation
Duangdara J., Boonsri B., Sayinta A., Supradit K., Thintharua P., Kumkate S., Suriyonplengsaeng C., Larbcharoensub N., Mingphruedhi S., Rungsakulkij N., Muangkaew P., Tangtawee P., Vassanasiri W., Suragul W., Janvilisri T., Tohtong R., Bates D.O., Wongprasert K. CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS. Pharmaceuticals Vol.17 No.1 (2024). doi:10.3390/ph17010009 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/95781
Title
CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS
Corresponding Author(s)
Other Contributor(s)
Abstract
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 Opisthorchis viverrini (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.