Biomaterial Database

Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response. 2018

Chao-Yuan Huang, and Feng-Shu Hsieh, and Cheng-Yi Wang, and Li-Ju Chen, and Shih-Shin Chang, and Ming-Hsien Tsai, and Man-Hsin Hung, and Chiung-Wen Kuo, and Chi-Ting Shih, and Tzu-I Chao, and Kuen-Feng Chen

Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Imaging and Radiological Technology, Yuanpei University, Hsinchu, Taiwan.

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

UI	MeSH Term	Description	Entries
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D008113	Liver Neoplasms	Tumors or cancer of the LIVER.	Cancer of Liver,Hepatic Cancer,Liver Cancer,Cancer of the Liver,Cancer, Hepatocellular,Hepatic Neoplasms,Hepatocellular Cancer,Neoplasms, Hepatic,Neoplasms, Liver,Cancer, Hepatic,Cancer, Liver,Cancers, Hepatic,Cancers, Hepatocellular,Cancers, Liver,Hepatic Cancers,Hepatic Neoplasm,Hepatocellular Cancers,Liver Cancers,Liver Neoplasm,Neoplasm, Hepatic,Neoplasm, Liver
D008297	Male		Males
D008819	Mice, Nude	Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses.	Athymic Mice,Mice, Athymic,Nude Mice,Mouse, Athymic,Mouse, Nude,Athymic Mouse,Nude Mouse
D010879	Piperazines	Compounds that are derived from PIPERAZINE.
D011725	Pyridines	Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D011836	Radiation Tolerance	The ability of some cells or tissues to survive lethal doses of IONIZING RADIATION. Tolerance depends on the species, cell type, and physical and chemical variables, including RADIATION-PROTECTIVE AGENTS and RADIATION-SENSITIZING AGENTS.	Radiation Sensitivity,Radiosensitivity,Sensitivity, Radiation,Tolerance, Radiation,Radiation Sensitivities,Radiation Tolerances,Radiosensitivities,Sensitivities, Radiation,Tolerances, Radiation
D011838	Radiation-Sensitizing Agents	Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells.	Radiation Sensitizer,Radiosensitizing Agent,Radiosensitizing Agents,Agents, Radiation-Sensitizing,Radiation Sensitizers,Radiation Sensitizing Agents,Radiation-Sensitizing Drugs,Radiation-Sensitizing Effect,Radiation-Sensitizing Effects,Radiosensitizing Drugs,Radiosensitizing Effect,Radiosensitizing Effects,Agent, Radiosensitizing,Agents, Radiation Sensitizing,Agents, Radiosensitizing,Drugs, Radiation-Sensitizing,Drugs, Radiosensitizing,Effect, Radiation-Sensitizing,Effect, Radiosensitizing,Effects, Radiation-Sensitizing,Effects, Radiosensitizing,Radiation Sensitizing Drugs,Radiation Sensitizing Effect,Radiation Sensitizing Effects,Sensitizer, Radiation,Sensitizers, Radiation,Sensitizing Agents, Radiation
D004260	DNA Repair	The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones.	DNA Damage Response
D006528	Carcinoma, Hepatocellular	A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested.	Hepatocellular Carcinoma,Hepatoma,Liver Cancer, Adult,Liver Cell Carcinoma,Liver Cell Carcinoma, Adult,Adult Liver Cancer,Adult Liver Cancers,Cancer, Adult Liver,Cancers, Adult Liver,Carcinoma, Liver Cell,Carcinomas, Hepatocellular,Carcinomas, Liver Cell,Cell Carcinoma, Liver,Cell Carcinomas, Liver,Hepatocellular Carcinomas,Hepatomas,Liver Cancers, Adult,Liver Cell Carcinomas