Oncotarget

Research Papers:

BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells

Chieh-Yuan Cheng, Chung-Ji Liu, Yu-Chuen Huang, Shu-Hua Wu, Hsu-Wei Fang and Yu-Jen Chen _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:21231-21243. https://doi.org/10.18632/oncotarget.25035

Metrics: PDF 647 views  |   HTML 1243 views  |   ?  


Abstract

Chieh-Yuan Cheng1,2,3, Chung-Ji Liu2,3, Yu-Chuen Huang4,5, Shu-Hua Wu6, Hsu-Wei Fang7,8 and Yu-Jen Chen5,6,9

1Graduate Institute of Engineering Technology, National Taipei University of Technology, Taipei 10608, Taiwan

2Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan

3Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11221, Taiwan

4School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

5Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan

6Department of Medical Research, Mackay Memorial Hospital, New Taipei City 25160, Taiwan

7Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 10608, Taiwan

8Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County 35053, Taiwan

9Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 10449, Taiwan

Correspondence to:

Yu-Jen Chen, email: chenmdphd@gmail.com

Hsu-Wei Fang, email: hwfang@ntut.edu.tw

Keywords: BI2536; mitotic catastrophe; oral cancer; PLK1; radiosensitization

Received: August 15, 2017     Accepted: March 19, 2018     Published: April 20, 2018

ABSTRACT

BI2536 has been developed as a potential therapeutic agent for various cancers but not in oral cancer cells. Since BI2536 exhibits mitosis-regulating activity which are the most radiosensitive, we hypothesized that BI2536 might modulate the radiosensitivity of oral cancer cells. Human normal fibroblasts, oral cancer SAS, and OECM1 cells were treated with BI2536 (0–50 nM) and/or radiation (0–4 Gy). MTT assay, Liu’s staining, flow cytometry, clonogenic assay, Annexin V/propidium iodide (PI) staining, western blot analysis, and small interfering RNA knockdown experiments were used to assess cell viability, morphology, cell cycle progression, radiation survival, and expression of regulatory proteins in vitro. Male BALB/c nude mice implanted with SAS cells were used to examine the effects of BI2536 in vivo. Treatment with BI2536 preferentially inhibited the viability of SAS and OECM1 cells, but not the normal fibroblasts. Morphological examination and Annexin V/PI staining of BI2536-treated oral cancer cells showed mitotic catastrophe and apoptosis. A DNA histogram revealed BI2536 induced G2/M and upregulation of phosphorylated H3 indicating accumulation in the M phase. BI2536 modulated the expression of PLK1, cell division control protein (Cdc)2, Cdc20, Cdc25c, adenomatous polyposis coli 3, and cyclin B1. At 10 nM, BI2536 exhibited low cytotoxicity, effectively induced mitotic catastrophe, and more importantly, sensitized oral cancer cells to radiotherapy. The animal study showed that BI2536 (10 mg/kg) + radiation (2 Gy) resulted in stronger tumor inhibition than that associated with radiation alone. Our findings showed that BI2536 could be an effective radiosensitizer both in vitro and in vivo.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 25035