INTRODUCTION AND OBJECTIVES: Osteosarcoma (OS) is an aggressive malignancy that is the most common primary bone tumor in children. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in orthopaedic surgery to reduce pain and inflammation. NSAIDs have been shown to be toxic to certain malignancies such as colorectal, breast, and pancreatic cancers, as well as acute myeloid leukemia, but are not well-studied in OS. The purpose of this study is to assess whether ketorolac and indomethacin induce apoptosis in OS cells, compare this to a control and explore the underlying mechanism.

METHODS: A rat OS cell line (UMR-108) was exposed to various concentrations of both ketorolac and indomethacin. Both ketorolac and indomethacin were compared to a pH buffered saline control. The background death rate of the control was subtracted from the test samples. Cell viability, cytotoxicity, apoptosis induction, DNA fragmentation and the expression of apoptosis-related markers were examined by MTT assay, colony formation assay, flow cytometry, agarose gel electrophoresis, and western blot respectively.

RESULTS: The results demonstrate that ketorolac and indomethacin induce apoptosis of rat OS cells in a dose-and time-dependent manner. Apoptosis was confirmed by cell morphology and annexin positivity. Both NSAIDs induced morphological changes in OS cells and decreased their capacity to form colonies. The molecular data showed that the NSAIDs affected expression of Bcl-2, survivin, and PARP. Caspase-3 was also decreased as shown in Figure 1.

CONCLUSIONS: This study showed that both ketorolac and indomethacin caused a decrease in OS cell viability and an increase in apoptosis in a time-and dose-dependent matter. NSAIDs are well-studied, inexpensive and readily available with well known side effect profiles. Due to these characteristics, additional in vitro and in vivo research studies are warranted to identify the use of these medications in the treatment of OS in the clinical setting.



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