Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Chem Biol Drug Des. 2021 Jan;97(1):77-86. doi: 10.1111/cbdd.13762. Epub 2020 Jul 28.
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 (IC = 11 µm) and the limonoid toosendanin (IC = 26 nm). Other statins and limonoids were then tested, and cerivastatin was identified as a particularly potent (IC < 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.
建立了一种高通量筛选测定法，并将其应用于大量天然产物提取物样品库，以鉴定出与低转移性亲本细胞系（MG63）相比，优先抑制体外 2D 生长的化合物具有高转移性骨肉瘤细胞系（MG63.3）。用生物测定指导的分级分离对差异活性天然产物提取物进行评估，导致鉴定出洛伐他汀（IC = 11 µm）和番荔枝素 toosendanin（IC = 26 nm）。然后测试了其他他汀类药物和柠檬素，发现西立伐他汀是一种特别有效（IC < 0.1 µm）和选择性的试剂。这些化合物在 MG63.3 细胞中强烈且选择性地诱导细胞凋亡，但在 MG63 细胞中没有。用其他细胞对进行的测定用于检查这些结果的普遍性。他汀类药物和柠檬素可能代表了开发骨肉瘤转移调节剂的未开发机会。由于西立伐他汀先前已被批准用于临床用途，因此可以考虑在骨肉瘤中重新使用，等待在进一步的模型中验证。
