Pre-treatment of platinum resistant ovarian cancer cells with an MMP-9/MMP-2 inhibitor prior to cisplatin enhances cytotoxicity as determined by high content screening

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Abstract

Platinum resistance is a major cause of treatment failure in ovarian cancer. We previously identified matrix metalloproteinase 9 (MMP-9) as a potential therapeutic target of chemoresistant disease. A2780cis (cisplatin-resistant) and A2780 (cisplatin-sensitive) ovarian carcinoma cell lines were used. The cytotoxic effect of MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) alone or in combination with cisplatin was determined using high content screening. Protein expression was examined using immunohistochemistry and ELISA. Co-incubation of cisplatin and an MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino] -3 phenylpropionic acid (C21H19NO4S) resulted in significantly greater cytotoxicity as compared to either treatment alone in a cisplatin resistant MMP-9 overexpressing cell line; A2780cis. In addition, pre-incubating with MMP-9i prior to cisplatin further enhances the cytotoxic effect. No significant difference was observed in MMP-9 protein in tissue but a trend towards increased MMP-9 was observed in recurrent serum. We propose that MMP-9/MMP-2i may be utilized in the treatment of recurrent/chemoresistant ovarian cancers that overexpress MMP-9 mRNA but its role in vivo remains to be evaluated. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

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Laios, A., Mohamed, B. M., Kelly, L., Flavin, R., Finn, S., McEvoy, L., … O’Toole, S. A. (2013). Pre-treatment of platinum resistant ovarian cancer cells with an MMP-9/MMP-2 inhibitor prior to cisplatin enhances cytotoxicity as determined by high content screening. International Journal of Molecular Sciences, 14(1), 2085–2103. https://doi.org/10.3390/ijms14012085

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