Arenobufagin induces cell apoptosis by modulating the cell cycle regulator claspin and the JNK pathway in nasopharyngeal carcinoma cells

ABSTRACT

Background

The high recurrence rate and incidence of distant metastasis of nasopharyngeal carcinoma (NPC) result in poor prognosis. It is necessary to identify natural compounds that can complement combination radiation therapy. Arenobufagin is commonly used for heart diseases and liver cancer, but its effectiveness in NPC is unclear.

Study Design and Methods

The effect of arenobufagin-induced apoptosis was measured by a cell viability assay, tumorigenic assay, fluorescence assay, and Western blot assay through NPC-039 and NPC-BM cell lines. The protease array, Western blot assay, and transient transfection were used to investigate the underlying mechanism of arenobufagin-induced apoptosis. An NPC xenograft model was established to explore the antitumor activity of arenobufagin in vivo.

Results

Our findings indicated that arenobufagin exerted cytotoxic effects on NPC cells, inhibiting proliferation through apoptosis activation. Downregulation of claspin was confirmed in arenobufagin-induced apoptosis. Combined treatment with arenobufagin and mitogen-activated protein kinase inhibitors demonstrated that arenobufagin induced NPC apoptosis through the c-Jun N-terminal kinases (JNK) pathway inhibition. Furthermore, arenobufagin suppressed NPC tumor proliferation in vivo.

Conclusion

Our results revealed the antitumor effect of arenobufagin in vitro and in vivo. Arenobufagin may have clinical utility in treating NPC due to its suppression of claspin and inhibition of the JNK pathway.

KEYWORDS:

• Arenobufagin
• nasopharyngeal carcinoma
• apoptosis
• claspin
• JNK pathway

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2024.2348014

Authorship contribution statement

HY Ho: Writing – Original draft preparation, Methodology, Software, Writing – Reviewing and Editing. MK Chen: Conceptualization, Writing – Reviewing and Editing. CC Lin: Methodology, Software. YS Lo: Methodology, Software. YC Chuang: Methodology, Software. MJ Hsieh: Conceptualization, Writing – Original draft preparation, Writing – Reviewing and Editing.

Data availability statement

The datasets generated for this study are available on request to the corresponding authors.

Additional information

Funding

This research was supported by grants from National Science and Technology Council (MOST 111-2314-B-371-007-MY2) and Changhua Christian Hospital (111-CCH-IRP-006).