Inhibition of Polo-Like Kinase 1 by BI2536 Reverses the Multidrug Resistance of Human Hepatoma Cells In Vitro and In Vivo.

Abstract

BACKGROUND:

Multi Drug Resistance (MDR) is the phenomenon that cancers develop resistance to majority of chemotherapy drugs and is a serious obstacle to the treatment for Hepatocellular Carcinoma (HCC). Polo-Like Kinase 1 (PLK1) is a serine/threonine kinase associated with tumor growth and clinical prognosis in HCC and BI2536 is its potent inhibitor with IC50 of 0.83nM.

AIMS:

To test whether the down-regulation of PLK1 by its inhibitor BI2536 would have beneficial effects on the reversal of MDR in HCC cells.

METHODS:

The CCK-8 assay was used to determine the viability of HepG2/ADM and SMMC7721/ADM cells and their parental cells treated with BI2536. Then animal model studies were performed. Cell invasion assay and wound healing assay were used to determine the invasion ability and motility. Flow cytometric was used to test the apoptosis induced by BI2536. Western blot and quantitative real-time PCR were performed to test the change of expression of MDR and apoptosis-related gene.

RESULTS:

BI2536 down-regulated the expression of PLK1 protein and mRNA specifically. BI2536 can significantly reduce IC50 for ADM and other drugs in ADM-resistant HCC cells. Meanwhile, it inhibited cell viability, proliferation, and invasion, and induced cell cycle arrest and apoptosis in HCC cells with MDR.

CONCLUSION:

Our results suggest that PLK1 inhibitor BI2536 can re-sensitize HCC cancer cell with MDR through induction of apoptosis. Thus, PLK1 inhibitor BI2536 may act as an effective chemotherapeutic drug in the clinical treatment of HCC patients with MDR.

• Authors: Hui Y Li, Fei Luo, Xiao Y Li, Xi F Fu, Jie F He, Yan Z Tian, Jun J Zhu, Xin Y Chu, Hao L Zhao
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 19 Issue 6 Pg. 740-749 ( 2019) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 30836927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Antineoplastic Agents
• BI 2536
• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pteridines
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Liver Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Molecular Structure
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Pteridines (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured