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Effect of a Vitamin D3 derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model

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Summary

The objective of the present study was to test the hypothesis that Calcidiol derivative B3CD qualifies as a potential anti-cancer drug in vivo employing an ovarian cancer xenograft model in mice. In addition, the selectivity of B3CD on viability and proliferation of platinum-resistant human ovarian cancer cell lines in comparison to control cell lines was analyzed in vitro. B3CD displayed cell line-specific cytotoxicity screened against a panel of ovarian and other carcinoma cell lines, endothelial and control cells. B3CD, at sub-cytotoxic concentrations, revealed stronger effects on the proliferation of SKOV-3 ovarian cancer cells vs. primary fibroblasts as determined by BrdU incorporation analysis. Treatment with B3CD at 0.5 µM resulted in highly condensed chromatin and fragmented nuclei in SKOV-3 cells but not in primary fibroblasts. B3CD induced cell death at low drug concentrations (≤0.5 µM) in SKOV-3 ovarian cancer cells is mediated by the p38 MAPK signaling pathway: B3CD induced p38 MAPK expression and activation in SKOV-3 cells and inhibition of p38 signaling counteracted B3CD induced cell death in vitro. An ovarian cancer cell animal model (human SKOV-3 cell derived xenografts in nude mice) revealed that tumor growth in few B3CD treated mice accelerated while the majority of B3CD treated mice displayed delayed tumor growth or full tumor regression. B3CD possesses anti-ovarian cancer properties in vitro and in vivo. We propose the further development of non-calcemic bromoacetoxy derivatives of vitamin D3 as potential anti-cancer therapeutics.

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Acknowledgements

This work was supported by a Brown University Seed Grant and a NICHD, K12 HD043447 BIRCWH Scholar Grant to Dr. Brard. The authors thank NIH COBRE Grant 1-P20RR018728 for providing instrumentation support. This article is dedicated to Laila A. Lange.

Competing Interests

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Molecular Therapeutics Laboratory, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants’ Hospital of RI, Warren Alpert Medical School of Brown University, Providence, RI, 02905, USA

    Thilo S. Lange, Ashley R. Stuckey, Katina Robison, Kyu Kwang Kim, Rakesh K. Singh & Laurent Brard

  2. Division of Biology and Medicine, Brown University, Providence, RI, 02912, USA

    Thilo S. Lange

  3. Division of Research, Department of Obstetrics and Gynecology, Women and Infants’ Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, 02905, USA

    Christina A. Raker

  4. Molecular Therapeutics Laboratory, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of RI, 101 Dudley Street, Providence, RI, 02905, USA

    Laurent Brard

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  1. Thilo S. Lange
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  2. Ashley R. Stuckey
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  7. Laurent Brard
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Correspondence to Laurent Brard.

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Lange, T.S., Stuckey, A.R., Robison, K. et al. Effect of a Vitamin D3 derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model. Invest New Drugs 28, 543–553 (2010). https://doi.org/10.1007/s10637-009-9284-y

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  • DOI: https://doi.org/10.1007/s10637-009-9284-y

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