Open Access

Single‑agent nintedanib suppresses metastatic osteosarcoma growth by inhibiting tumor vascular formation

  • Authors:
    • Takatsune Shimizu
    • Atsunobu Sagara
    • Yumi Fukuchi
    • Akihiro Muto
  • View Affiliations

  • Published online on: January 25, 2024     https://doi.org/10.3892/ol.2024.14254
  • Article Number: 123
  • Copyright: © Shimizu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

New therapeutic approaches are needed for osteosarcoma, which is the most common malignancy of the bone, especially for metastatic cases. Nintedanib is a potent, oral tyrosine kinase inhibitor approved for treating idiopathic pulmonary fibrosis, which blocks a variety of receptor signals, including fibroblast growth factor receptors, vascular endothelial growth factor receptors and platelet‑derived growth factor receptors. The present study assessed the effect of nintedanib on previously developed mouse AXT osteosarcoma cells, and on AXT‑derived osteosarcoma developed in C57BL/6 mice, which displays lethal tumors with osteoid formation and lung metastatic lesions that mimics human disease. In vitro analysis, including flow cytometry and immunoblotting, revealed that nintedanib inhibited AXT cell proliferation and cell cycle progression, induced apoptosis, and inactivated AKT and ERK1/2. Immunoblot analysis using tumor lysates demonstrated that nintedanib inhibited its target molecules in vivo. As a single agent, nintedanib decreased the size of primary AXT‑derived osteosarcoma, and reduced circulating tumor cells and lung metastasis. Immunohistochemical findings indicated that nintedanib exerted antitumor activity mainly by inhibiting the formation of CD31‑positive tumor vasculature, while αSMA‑positive cells were still enriched in tumors after nintedanib treatment. In addition, nintedanib exhibited an anti‑osteosarcoma effect on C57BL/6 severe combined immunodeficient mice in which T‑ and B‑cell function is obsolete, suggesting that the antitumor effect of nintedanib was not attributable to antitumor immunity. Collectively, these findings indicated that nintedanib holds potential for treating osteosarcoma.
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March-2024
Volume 27 Issue 3

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Spandidos Publications style
Shimizu T, Sagara A, Fukuchi Y and Muto A: Single‑agent nintedanib suppresses metastatic osteosarcoma growth by inhibiting tumor vascular formation. Oncol Lett 27: 123, 2024
APA
Shimizu, T., Sagara, A., Fukuchi, Y., & Muto, A. (2024). Single‑agent nintedanib suppresses metastatic osteosarcoma growth by inhibiting tumor vascular formation. Oncology Letters, 27, 123. https://doi.org/10.3892/ol.2024.14254
MLA
Shimizu, T., Sagara, A., Fukuchi, Y., Muto, A."Single‑agent nintedanib suppresses metastatic osteosarcoma growth by inhibiting tumor vascular formation". Oncology Letters 27.3 (2024): 123.
Chicago
Shimizu, T., Sagara, A., Fukuchi, Y., Muto, A."Single‑agent nintedanib suppresses metastatic osteosarcoma growth by inhibiting tumor vascular formation". Oncology Letters 27, no. 3 (2024): 123. https://doi.org/10.3892/ol.2024.14254