BI6727 and GSK461364A, potent PLK1 inhibitors induce G2/M arrest and apoptosis against cholangiocarcinoma cell lines

Handy Riantana; Orawan Waenphimai; Panupong Mahalapbutr; Kun Karnchanapandh; Kulthida Vaeteewoottacharn; Sopit Wongkham; Kanlayanee Sawanyawisuth

doi:10.1016/j.prp.2023.154678

BI6727 and GSK461364A, potent PLK1 inhibitors induce G2/M arrest and apoptosis against cholangiocarcinoma cell lines

Pathol Res Pract. 2023 Aug:248:154678. doi: 10.1016/j.prp.2023.154678. Epub 2023 Jul 8.

Authors

Handy Riantana¹, Orawan Waenphimai¹, Panupong Mahalapbutr¹, Kun Karnchanapandh², Kulthida Vaeteewoottacharn¹, Sopit Wongkham¹, Kanlayanee Sawanyawisuth³

Affiliations

¹ Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
² Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
³ Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: kanlayanee@kkumail.com.

PMID: 37454493
DOI: 10.1016/j.prp.2023.154678

Abstract

Polo-like kinase 1 (PLK1) is an essential mitotic checkpoint protein that plays a key role in cell cycle division. Overexpression of PLK1 has been associated with poor prognosis in various cancers. Cholangiocarcinoma (CCA) is a lethal bile duct cancer and the current treatments in inoperable patients have not been satisfactory. In order to develop novel targeted therapies, we investigated the efficacy of BI6727 (volasertib) and GSK461364A, polo-like kinase 1 (PLK1) inhibitors in KKU-100 and KKU-213A CCA cell lines. PLK1 expression was significantly up-regulated in CCA cases compared with normal tissues based on the results derived from GEPIA. Western blot results exhibited PLK1 protein expression in both CCA cell lines. Molecular dynamics simulations and free energy calculations based on MM/GBSA method revealed that BI6727-PLK1 and GSK461364A-PLK1 complexes were stable in an aqueous environment, and their complexation was mainly driven by Van der Waals interaction. BI6727 and GSK461364A clearly suppressed CCA cell proliferation and induced G2/M arrest, accompanied with upregulation of cyclin B1 and phosphorylated Histone H3 at Ser10 (pS10H3), specific markers of mitosis. Furthermore, both compounds triggered mitotic catastrophe followed by cell apoptosis via activation of PARP and Caspase 3, as well as downregulation of Mcl-1 anti-apoptotic protein in both CCA cell lines. In conclusion, pharmacologic PLK1 inhibition by BI6727 and GSK461364A blocked survival of CCA cells by several mechanisms. Our study provides evidence that BI6727 and GSK461364A could be alternative drugs and have potential implications at the clinical level for CCA therapy.

Keywords: Apoptosis; BI6727; Cholangiocarcinoma; GSK461364A; Mitotic catastrophe; PLK1; Volasertib.

MeSH terms

Apoptosis
Bile Duct Neoplasms* / drug therapy
Bile Duct Neoplasms* / pathology
Bile Ducts, Intrahepatic / pathology
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation
Cholangiocarcinoma* / drug therapy
Cholangiocarcinoma* / pathology
G2 Phase Cell Cycle Checkpoints
Humans
Polo-Like Kinase 1

Substances

GSK 461364A
Cell Cycle Proteins