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

Authors

• 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

Language

English

Publication Date

12-20-2023

Journal

Pharmaceuticals

DOI

10.3390/ph17010009

PMID

38275995

PMCID

PMC10821224

PubMedCentral® Posted Date

12-20-2023

PubMedCentral® Full Text Version

Post-print

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.

Keywords

cholangiocarcinoma, Opisthorchis viverrini, CP-673451, PDGFR inhibitor, Nrf2

Published Open-Access

yes

Recommended Citation

Duangdara, Jinchutha; Boonsri, Boonyakorn; Sayinta, Apinya; et al., "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" (2023). Faculty, Staff and Students Publications. 8471.
https://digitalcommons.library.tmc.edu/baylor_docs/8471