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KMID : 0613320090150020111
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Journal of the Korean Bone and Joint Tumor Soceity
2009 Volume.15 No. 2 p.111 ~ p.121
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Effects of Ibandronate on the Expression of Matrix Metalloproteinases in Human U2OS Osteosarcoma Cells
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Jung Sung-Taek
Seo Hyoung-Yeon
Xin Zeng-Feng
Kim Yang-Kyung
Kim Hyung-Won
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Abstract
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Background: Osteosarcoma is one of the most common primary malignant tumors of bone occurring mainly in children and adolescents. Although surgery combined with chemotherapy has markedly improved patient survival during the last years, the use of anticancer drugs is still associated with serious problem, such as the frequent acquisition of drug-resistant phenotypes and occurrence of “secondary malignancies”. Several solid tumors display enhanced expression of matrix metalloproteinases (MMPs), and recently clinical trials have been initiated on MMPinhibitors. On the other hand, bisphosphonates (BPs) are inhibitors of bone resorption, and widely used to treat osteoclast-mediated bone diseases. Also they appear to possess direct antitumor activity.
Methods: One osteosarcoma cell line (U2OS) was treated with ibandronate (0, 0.1, 1, 10 M) for 48 hours. Cell viabilities were determined using MTT assay, the mRNA levels of MMP-2 and MT1-MMP were detected by reverse-transcription polymerase chain reaction, the amount of MMP-2 and MT1-MMP protein were measured by Westernblot, the activities of MMP-2 were observed by Gelatin zymography, and Matrigel invasion assays were used to investigate the invasive potential of osteosarcoma cell lines before and after ibandronate treatment.
Results: The invasiveness of U2OS cell line was reduced dose-dependently following 48 hour treatment of up to 10 M of the ibandronate at which concentration no cytotoxicity occurred. Furthermore, the gelatinolytic activities and protein and mRNA levels of MMP-2 and MT1- MMP were also suppressed by increasing ibandronate concentrations.
Conclusion: Given that MMP-2 is instrumental in tumor cell invasion, it is very likely that the reduction in osteosarcoma cell invasion by ibandronate is a consequence, at least in part, of suppressed expression of both MMP-2 and MT1-MMP. Isolation of a molecule (s) responsible for the bisphosphonate inhibition of tumor cell invasion would pave the way for the development of a new generation of metastasis inhibitors.
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KEYWORD
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Osteosarcoma, Matrix metalloproteinase, Ibandronate
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