Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response.

Abstract

AIM:

Palbociclib is an oral cyclin-dependent kinase 4/6 inhibitor, which is efficacious in treating breast cancer. Currently, there are numerous active clinical trials testing palbociclib alone or in combination with other medications for treating various types of malignancies. Here, we evaluated the anti-cancer effect of palbociclib in combination with radiation therapy (RT) for treating human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) and addressed the molecular mechanism behind the combination therapy.

METHODS:

Immunofluorescence staining of γH2AX or 53BP1 was used to determine the effect of palbociclib on double-strand break (DSB) repair. Clonogenic assays, sphere formation and cell death ELISA were performed to study the sensitising effect of palbociclib on radiation-induced cytotoxicity. Signal alteration in DSB repair pathways was examined by Western blot analysis. Finally, we evaluated the in vivo anti-cancer activity and the associated molecular events of the combination therapy in a preclinical HCC xenograft model.

RESULTS:

Palbociclib affected the kinetics of DNA repair and enhanced the radiation sensitivity of HCC and CCA cells. Importantly, we found that palbociclib inhibits ataxia telangiectasia-mutated (ATM) kinase, the key upstream kinase responding to RT-induced DSBs. Furthermore, we showed that the inhibitory effect of palbociclib on RT-induced ATM kinase activation is mediated by protein phosphatase 5 (PP5). Both in vitro and in vivo investigations revealed that the inhibition of the PP5-ATM axis by palbociclib after DNA damage is responsible for the synergism between palbociclib and RT.

CONCLUSION:

Our findings provide a novel combination strategy against liver cancer cells. Clinical trials using palbociclib as an adjuvant in RT are warranted.

• Authors: Chao-Yuan Huang, Feng-Shu Hsieh, Cheng-Yi Wang, Li-Ju Chen, Shih-Shin Chang, Ming-Hsien Tsai, Man-Hsin Hung, Chiung-Wen Kuo, Chi-Ting Shih, Tzu-I Chao, Kuen-Feng Chen
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 102 Pg. 10-22 (Oct 2018) ISSN: 1879-0852 [Electronic] England
• PMID: 30103095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• H2AX protein, human
• Histones
• Piperazines
• Protein Kinase Inhibitors
• Pyridines
• Radiation-Sensitizing Agents
• TP53BP1 protein, human
• Tumor Suppressor p53-Binding Protein 1
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• palbociclib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, metabolism)
• Bile Duct Neoplasms (enzymology, genetics, pathology, therapy)
• Carcinoma, Hepatocellular (enzymology, genetics, pathology, therapy)
• Cell Line, Tumor
• Chemoradiotherapy
• Cholangiocarcinoma (enzymology, genetics, pathology, therapy)
• DNA Breaks, Double-Stranded
• DNA Repair (drug effects)
• Histones (metabolism)
• Humans
• Kinetics
• Liver Neoplasms (enzymology, genetics, pathology, therapy)
• Male
• Mice, Nude
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• Radiation Tolerance
• Radiation-Sensitizing Agents (pharmacology)
• Tumor Suppressor p53-Binding Protein 1 (metabolism)
• Xenograft Model Antitumor Assays