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Effect of a V-ATPase inhibitor, FR202126, in syngeneic mouse model of experimental bone metastasis

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Abstract

Purpose

It has been demonstrated that vacuolar ATPase (V-ATPase) is involved in various aspects of bone metastasis. The aim of this study is to investigate the effect of the anti-bone resorptive activity of the V-ATPase inhibitor FR202126 on bone metastases in mice with metastatic breast cancer.

Method

As a spontaneous model of breast cancer metastasis to bone, mouse breast cancer cells, 4T1, were injected into the mammary fat pad in immunocompetent syngeneic mice. The mice were orally treated with FR202126 for 29 days. Tumor volume was measured once a week. Thirty days after the injection of the cells, the bone mineral density (BMD) of the proximal tibia was measured using peripheral quantitative computed tomography. Histomorphometric analysis of the distal femurs and the proximal tibiae was performed. To elucidate the mechanism behind the anti-osteolytic effect of FR202126, 4T1 cells were treated directly in vitro with FR202126. Cell viability was measured, and cell invasion was assessed using matrigel.

Results

Oral administration of FR202126 significantly increased BMD by reducing the eroded bone surface ratio. While FR202126 is known to potently inhibit osteoclast mediated bone resorption, it did not prevent invasion by cancer cells or their proliferation.

Conclusion

The V-ATPase inhibitor FR202126 was found to be effective at ameliorating osteolysis induced by metastatic breast cancer, even when the cancer cells themselves are not significantly affected by it. These results suggest that the anti-bone resorptive effect of the V-ATPase inhibitor might be useful for treating bone metastases associated with breast cancer.

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  1. Data Management and Regulatory Support Department, Astellas Research Service Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan

    Kazuaki Niikura

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  1. Kazuaki Niikura
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Correspondence to Kazuaki Niikura.

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Niikura, K. Effect of a V-ATPase inhibitor, FR202126, in syngeneic mouse model of experimental bone metastasis. Cancer Chemother Pharmacol 60, 555–562 (2007). https://doi.org/10.1007/s00280-006-0401-8

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  • DOI: https://doi.org/10.1007/s00280-006-0401-8

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