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Antitumor effects of BI-D1870 on human oral squamous cell carcinoma

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Abstract

Purpose

Among the signaling pathways implicated in the tumorigenesis of oral squamous cell carcinoma (OSCC) is the extracellular signal-regulated kinase mitogen-activated protein kinase pathway, a downstream target of which is a family of serine/threonine kinases known as the 90 kDa ribosomal S6 kinases (RSKs). This study aims to investigate the role of BI-D1870, a specific inhibitor of p90 RSKs, in a panel of OSCC cell lines.

Methods

The antitumor effects and mechanisms of BI-D1870 were assessed by MTT assays, flow cytometry, Western blotting, transfection, and confocal microscopy.

Results

BI-D1870 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound inhibited the downstream RSK target YB-1 and caused apoptosis as evidenced by PARP cleavage, activation of the caspase cascade, and the presence of pyknotic nuclei in the 4,6-diamidino-2-phenylindole assay. In addition, BI-D1870 also induced G2/M arrest by modulating the expression of p21 and other cell cycle regulators. Other newly discovered anticancer attributes of BI-D1870 included the generation of reactive oxygen species and increases in endoplasmic reticulum stress and autophagy.

Conclusions

Together, these results suggest the translational value of BI-D1870 in oral squamous cell carcinoma therapy.

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Acknowledgments

This work was supported in part by grants from the Taiwan Department of Health, China Medical University Hospital Cancer Research of Excellence (DOH102-TD-C-111-005), National Science Council Grant (NSC 101-2320-B-039-029-MY2), China Medical University (CMU98-S52), and China Medical University Hospital (DMR-99-304, DMR-101-008).

Conflict of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, 40402, Taiwan

    Chang-Fang Chiu & Li-Yuan Bai

  2. Cancer Center, China Medical University Hospital, Taichung, 40402, Taiwan

    Chang-Fang Chiu

  3. Department of Oral and Maxillofacial Surgery, China Medical University Hospital, Taichung, 40402, Taiwan

    Michael Yuanchien Chen

  4. Department of Biological Science and Technology, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan

    Shih-Yuan Peng, Chia-Yung Wu & **g-Ru Weng

  5. School of Medicine, China Medical University, Taichung, 40402, Taiwan

    Chang-Fang Chiu & Li-Yuan Bai

  6. School of Dentistry, China Medical University, Taichung, 40402, Taiwan

    Michael Yuanchien Chen

  7. Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH, 43210, USA

    Naval Kapuriya

  8. Preclinical Services, Charles River Laboratories, Spencerville, OH, 45887, USA

    Aaron M. Sargeant

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  1. Chang-Fang Chiu
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  8. **g-Ru Weng
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Correspondence to **g-Ru Weng.

Additional information

Chang-Fang Chiu and Li-Yuan Bai have contributed equally to this work.

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Chiu, CF., Bai, LY., Kapuriya, N. et al. Antitumor effects of BI-D1870 on human oral squamous cell carcinoma. Cancer Chemother Pharmacol 73, 237–247 (2014). https://doi.org/10.1007/s00280-013-2349-9

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  • DOI: https://doi.org/10.1007/s00280-013-2349-9

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