Identification of potential modulators of osteosarcoma metastasis by high‐throughput cellular screening of natural products. (28th July 2020)

• Record Type: Journal Article
• Authors: Long, Sarah A.; Huang, Shan; Kambala, Anusha; Ren, Ling; Wilson, Jennifer; Goetz, Michael; Hao, Xiaojiang; Yang, Xiaosheng; Goncharova, Ekaterina I.; Jia, Libin; LeBlanc, Amy; Khanna, Chand; Henrich, Curtis J.; Beutler, John A.
• Is Part Of: Chemical biology & drug design. Volume 97:Number 1(2021)
• Page Start: 77
• Page End: 86
• Publication Date: 2020-07-28
• Subjects: high‐throughput screening -- limonoids -- metastasis -- osteosarcoma -- statins; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13762
• Languages: English
• ISSNs: 1747-0277

Abstract

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 compounds 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. As cerivastatin was previously approved for clinical use, it could be considered for repurposing in osteosarcoma, pending validation in further models. Abstract : An HTS assay of natural products identified samples preferentially inhibiting growth of highly metastatic osteosarcoma cells compared to parental cells of low metastatic potential. This led to the identification of lovastatin and toosendanin; other statins and limonoids were tested, and cerivastatin was identified as particularly potent and selective, selectively inducing apoptosis in high metastatic cells. Cerivastatin was previously approved for clinical use, and could be repurposed in osteosarcoma.