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, Yu Jen Chen

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)21231-21243
Number of pages13
JournalOncotarget
Volume9
Issue number30
DOIs
Publication statusPublished - Apr 20 2018
Externally publishedYes

Keywords

  • BI2536
  • Mitotic catastrophe
  • Oral cancer
  • PLK1
  • Radiosensitization

ASJC Scopus subject areas

  • Oncology

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