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

Alexandros Laios⁴  Bashir M. Mohamed²  Lynne Kelly⁴  Richard Flavin¹  Stephen Finn¹  Lynda McEvoy⁴  Michael Gallagher¹  Cara Martin¹  Orla Sheils¹  Martina Ring¹  Anthony Davies²  Margaret Lawson³  Noreen Gleeson⁴  Tom D𠆚rcy⁴  Charles d�hemar¹  Lucy Norris⁴  Ream Langhe⁴  Feras Abu Saadeh⁴  John J. O’Leary¹ 

[1] Department of Histopathology, Trinity College Dublin, Sir Patrick Duns Research Laboratory, St. James’s Hospital and The Coombe Women and Infants University Hospital, Dublin 8, Ireland; E-Mails:;Department of Clinical Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland; E-Mails:;Department of Histopathology, St. James’s Hospital, Dublin 8, Ireland; E-Mail:;Department of Obstetrics and Gynaecology, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland; E-Mails:

关键词: ovarian;    MMP-9/MMP-2 inhibitor;    chemoresistance;    recurrent;    high content screening;   

DOI  :  10.3390/ijms14012085

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.