title: 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.
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.
authors: Department of Obstetrics and Gynaecology, Trinity College Dublin, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland. olearyjj@tcd.ie.
authors: Alexandros
authors: A
authors: Laios
authors: Bashir M
authors: BM
authors: Mohamed
authors: Lynn
authors: L
authors: Kelly
authors: Richard
authors: R
authors: Flavin
authors: Stephen
authors: S
authors: Finn
authors: Lynda
authors: L
authors: McEvoy
authors: Michael
authors: M
authors: Gallagher
authors: Cara
authors: C
authors: Martin
authors: Orla
authors: O
authors: Sheils
authors: Martina
authors: M
authors: Ring
authors: Anthony
authors: A
authors: Davies
authors: Margaret
authors: M
authors: Lawson
authors: Noreen
authors: N
authors: Gleeson
authors: Tom
authors: T
authors: D'Arcy
authors: Charles
authors: C
authors: d'Adhemar
authors: Lucy
authors: L
authors: Norris
authors: Ream
authors: R
authors: Langhe
authors: Feras Abu
authors: FA
authors: Saadeh
authors: John J
authors: JJ
authors: O'Leary
authors: Sharon A
authors: SA
authors: O'Toole
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D002945:Cisplatin