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Targeting X chromosome-linked inhibitor of apoptosis protein in mucoepidermoid carcinoma of the head and neck: A novel therapeutic strategy using nitidine chloride

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Abstract

Nitidine chloride (NC) was recently reported to exhibit a wide range of pharmacological properties for several diseases, including cancer. Here we report for the first time that NC is a potential therapeutic agent for mucoepidermoid carcinoma (MEC) occurring in the head and neck because it suppresses X chromosome-linked inhibitor of apoptosis protein (XIAP) in human MEC in vitro and in vivo. The antitumor effects of NC were evaluated by trypan blue exclusion assay, western blotting, live/dead assay, 4’,6-diamidino-2-phenylindole (DAPI) staining, human apoptosis antibody array, immunofluorescence staining, immunohistochemistry, small interfering RNA assay, transient transfection of XIAP overexpression vector, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and histopathological examination of organs. NC inhibited cell viability and induced caspase-dependent apoptosis in vitro. A human apoptosis antibody array assay showed that XIAP is suppressed by NC treatment. XIAP was overexpressed in oral squamous cell carcinoma (OSCC) tissues that arose from the head and neck, and high XIAP expression was correlated with poor prognosis in OSCC patients. XIAP depletion significantly increased apoptosis, and ectopic XIAP overexpression attenuated the apoptosis induced by NC treatment. NC suppressed tumor growth in vivo at a dosage of 5 mg/kg/day. The number of TUNEL-positive cells increased and the protein expression of XIAP was consistently downregulated in NC-treated tumor tissues. In addition, NC caused no histopathological changes in the liver or kidney. These findings provide new insights into the mechanism of action underlying the anticancer effects of NC and demonstrate that NC is a promising therapeutic agent for the treatment of human MEC of the head and neck.

Key messages

• Nitidine chloride induces caspase-dependent apoptosis in MEC of the head and neck.

• High XIAP expression correlates with poor prognosis of OSCC patients.

• Nitidine chloride suppresses tumor growth in vivo without any systemic toxicities.

• Targeting XIAP is a novel chemotherapeutic strategy for MEC of the head and neck.

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Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science ICT and Future Planning [2019R1A2C1085896 and 2020R1C1C1005480].

Author information

Author notes

  1. Hye-Jeong Kwon and Kyungsil Yoon contributed equally to this work.

Authors and Affiliations

  1. Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea

    Hye-Jeong Kwon, In-Hyoung Yang, Seong Doo Hong, Ji-Ae Shin & Sung-Dae Cho

  2. Comparative Biomedicine Research Branch, Division of Translational Science, National Cancer Center, Goyang, 10408, Republic of Korea

    Kyungsil Yoon

  3. Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, 32439, Republic of Korea

    Ji-Youn Jung, Sung-Hyun Kim & Eun-Seon Yoo

  4. Department of Oral Pathology, School of Dentistry, Yangsan Campus of Pusan National University, Yangsan, 50612, Republic of Korea

    Mi Heon Ryu

  5. Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea

    So-Young Choi

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  1. Hye-Jeong Kwon
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Contributions

H.J.K. and K.Y. conducted most of the experiments with assistance from J.Y.J., M.H.R., and J.A.S.; H.J.K., K.Y., S.H.K., E.S.Y., and S.Y.C. analyzed the data. M.H.R. and S.D.H. interpreted the data and performed statistical analysis. H.J.K. and J.A.S drafted the manuscript. J.A.S. and S.D.C. designed, supervised, and wrote the final draft of the paper. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Ji-Ae Shin or Sung-Dae Cho.

Ethics declarations

Clinical samples were approved by the Institutional Review Board of Pusan National University Yangsan Hospital (IRB approval number: PNUDH-2018-016) and animal study was in accordance with the Institutional Animal Care and Use Committee (IACUC) guidelines approved by Kongju National University (IACUC approval number: KNU2018-4).

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Kwon, HJ., Yoon, K., Jung, JY. et al. Targeting X chromosome-linked inhibitor of apoptosis protein in mucoepidermoid carcinoma of the head and neck: A novel therapeutic strategy using nitidine chloride. J Mol Med 98, 1591–1602 (2020). https://doi.org/10.1007/s00109-020-01977-w

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  • DOI: https://doi.org/10.1007/s00109-020-01977-w

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