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.

TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling

“…Multiple downstream TWIST1 target genes have been implicated in drug resistance, including interleukin 8 and matrix metalloproteinases 2 and 9141516. Additionally, TWIST1 has been shown to regulate Gli1, which upregulates the DNA repair protein ERCC1.…”

Knowledge-guided gene prioritization reveals new insights into the mechanisms of chemoresistance

“…As another example MMP2, a member of the matrix metalloproteinase family involved in the breakdown of the extracellular matrix, was ranked 9 using ProGENI, while Pearson correlation analysis did not place it among the top 15. An inhibitor of MMP2 has been shown to significantly increase cytotoxicity in cisplatin resistant ovarian carcinoma cell line, A2780cis [30]. In addition to the 9 (of 15) genes with direct literature evidence, our own experiments revealed that knockdown of three of the remaining 6 predicted genes, TUBB6, DYNC2H1, and ELK3, significantly sensitized both cell lines to cisplatin treatment ( Fig.…”

“…These figures are drawn using Cytoscape [89]. shown to significantly increase cytotoxicity in cisplatin resistant ovarian carcinoma cell line, A2780cis [30]. In addition to the 9 (of 15) genes with direct literature evidence, our own experiments revealed that knockdown of three of the remaining 6 predicted genes, TUBB6, DYNC2H1, and ELK3, significantly sensitized both cell lines to cisplatin treatment (Fig.…”

The effect of adenomyosis on the outcomes of laparoscopic hysterectomy

“…MMPs are proteolytic enzymes, which have the potential capacity of degrading the extracellular matrix (ECM) components (28). In particular, MMP-2 and MMP-9 disintegrate type-IV collagen, which is the main component of the basement membrane (29). A study has demonstrated a marked increase in MMP-2 and MMP-9 levels in the ADS tissue (3).…”