Identification of Potential Modulators of Osteosarcoma Metastasis by High Throughput Cellular Screening of Natural Products

Author:

Long, Sarah A

Huang, Shan

Kambala, Anusha

Ren, Ling

Wilson,Jennifer

Goetz, Michael

Hao, Xiaojiang

Yang, Xiaosheng

Goncharova,Katya

Jia, Libin

LeBlanc, Amy

Khanna, Chand

Henrich,Curtis

Beutler,John [ORCID]
Author Address

Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, US., Glaxo Smith Kline, Upper Providence, PA, US., Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, US., Natural Products Discovery Institute, Doylestown, PA, US., Key Laboratory of Chemistry for Natural Products in Guizhou Province, China Academy of Sciences, Gui Yang, China., Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, US., Office of Cancer Complementary and Alternative Medicine, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, US., Ethos Veterinary Health and Ethos Discovery, Woburn MA and San Diego, CA, US., Basic Research Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, US.,

Abstract:

A high throughput screening assay was developed and applied to a large library of natural product extract samples, in order to identify compounds which preferentially inhibited the in vitro 2D growth of a highly metastatic osteosarcoma cell line (MG63.3) compared to a cognate parental cell line (MG63) with low metastatic potential. Evaluation of differentially active natural product extracts with bioassay guided fractionation led to the identification of lovastatin (IC50 = 11 µM) and the limonoid toosendanin (IC50 = 26 nM). Other statins and limonoids were then tested, and cerivastatin was identified as a particularly potent (IC50 < 0.1 µM) and selective agent. These potently and selectively induced apoptosis in MG63.3 cells, but not MG63. Assays with other cell pairs were used to examine the generality of these results. Statins and limonoids may represent unexplored opportunities for development of modulators of osteosarcoma metastasis. Since cerivastatin was previously approved for clinical use, it could be considered for repurposing in osteosarcoma, pending validation in further models. This article is protected by copyright. All rights reserved.

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