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Bone-Bound Bisphosphonates Inhibit Proliferation of Breast Cancer Cells

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Abstract

Bisphosphonates are used in treating patients with breast cancer. In vitro studies have shown that bisphosphonates act directly on tumour cells, inhibiting cell proliferation and inducing apoptosis. In most such studies, drugs were added to culture media exposing cells to high bisphosphonate concentrations in solution. However, since bisphosphonates bind to bone hydroxyapatite with high affinity and remain bound for very long periods of time, these experimental systems are not an optimal model for the action of the drugs in vivo. The aim of this study was to determine whether bone-bound zoledronate has direct effects on adjacent breast cancer cells. Bone slices were pre-incubated with bisphosphonate solutions, washed, and seeded with cells of the breast cancer cell lines, MCF7 or MDA-MB-231. Proliferation was assessed by cell counts and thymidine incorporation for up to 72 h. Inhibition of the mevalonate pathway was tested by measuring the levels of unprenylated Rap1A, and apoptosis was examined by the presence of cleaved caspase-8 on western blots. The proliferation rate of breast cancer cells on zoledronate-treated bone was significantly lower compared to cells on control bone. Other bisphosphonates showed a similar inhibitory effect, with an order of potency similar to their clinical potencies. Unprenylated Rap1A accumulated in MCF7 cells on zoledronate-treated bone, suggesting zoledronate acted through the inhibition of the mevalonate pathway. Accumulation of cleaved caspase-8 in MDA-MB-231 cells on bisphosphonate-treated bone indicated increased apoptosis in the cells. In conclusion, bone-bound zoledronate inhibits breast cancer cell proliferation, an activity that may contribute to its clinical anti-tumour effects.

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Acknowledgements

The authors acknowledge Mr. Greg Gamble for providing statistical advice and Dr. Yi Lance Xu for providing antibodies for Western blots. This study was funded by the Health Research Council of New Zealand (Grant 15/576 – Reid Mechanisms and Management of Musculoskeletal Disease).

Funding

This study was funded by the Health Research Council of New Zealand (Grant 15/576 – Reid Mechanisms and Management of Musculoskeletal Disease).

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  1. Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Young-Eun Park, Usha Bava, Jian-ming Lin, Jillian Cornish, Dorit Naot & Ian R. Reid

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YEP and JML performed the experimental research and analysis. UB contributed to the experimental work. JC, DN and IRR designed the study and the experimental plan. YEP prepared the first draft of the manuscript, DN, JC, UB, JML and IRR provided critical feedback and contributed to the final version.

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Correspondence to Ian R. Reid.

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Dr. Reid reports grants and personal fees from Amgen, personal fees and non-financial support from Novartis, outside the submitted work. Young-Eun Park, Usha Bava, Jian-ming Lin, Jillian Cornish and Dorit Naot declare that they have no conflict of interest.

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Park, YE., Bava, U., Lin, Jm. et al. Bone-Bound Bisphosphonates Inhibit Proliferation of Breast Cancer Cells. Calcif Tissue Int 105, 497–505 (2019). https://doi.org/10.1007/s00223-019-00590-5

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