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
, Lynda McEvoy 1,2, Michael Gallagher 2, Cara Martin 2, Orla Sheils 2, Martina Ring 2, Anthony Davies 3, Margaret Lawson 4, Noreen Gleeson 1, Tom D'Arcy 1, Charles d'Adhemar 2, Lucy Norris 1, Ream Langhe 1,2, Feras Abu Saadeh 1, John J. O'Leary 2,*
and Sharon A. O'Toole 1,2,*
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. View Full-Text
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Laios, A.; Mohamed, B.M.; Kelly, L.; Flavin, R.; Finn, S.; McEvoy, L.; Gallagher, M.; Martin, C.; Sheils, O.; Ring, M.; Davies, A.; Lawson, M.; Gleeson, N.; D'Arcy, T.; d'Adhemar, C.; Norris, L.; Langhe, R.; Saadeh, F.A.; O'Leary, J.J.; O'Toole, S.A. 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. Int. J. Mol. Sci. 2013, 14, 2085-2103.