Serous Ovarian Cancer (SOC): Methods Of Treatment

Here we sought to determine the relationship between STAT3 activity and Galectin-3 (Gal-3) and to investigate the cytotoxic effect of PectaSol-C Modified Citrus Pectin (Pect-MCP) as a specific competitive inhibitor of Galectin-3 (Gal-3) in combination with paclitaxel (PTX) to kill ovarian cancer cell multicellular tumor spheroid (MCTS). SKOV-3 cells in 2D and 3D culture were treated with exogenous Gal-3 for assessment of STAT3 activity. Two-way ANOVA main effect and IC50 of each drug Paclitaxel (PTX) and Pect-MCP or in combination were obtained from MTT assay results.

The phosphorylated STAT3 levels, migration, invasion, integrin mRNA and p-AKTser473 levels were assessed in the absence or presence of each drug alone or in combination. Gal-3 expression levels were assessed in human serous ovarian cancer (SOC) specimens and its correlation with different integrin mRNA levels was further assessed. Gal-3 triggered STAT3 phosphorylation and its expression was significantly increased in MCTS compared to monolayer SKOV-3 cells. Moreover, Pect-MCP synergized with PTX to kill SKOV3 MCTS and abrogated STAT3 activity.

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Moreover, Pect-MCP significantly reduced integrin mRNA levels leading to reduced AKT activity.

Accordingly, there were higher expression levels of Gal-3 in human high-grade SOC specimens compared to the normal ovary and borderline SOC which positively and significantly correlated with a5, b2 and b6 integrin mRNA levels. Together, these results revealed for the first time that Gal-3 triggers STAT3 activity and showed that Pect-MCP could be considered as a potential drug to enhance the PTX effect on ovarian cancer cells.

Ovarian cancer (OC) cells are disseminated throughout the abdominal cavity by peritoneal fluid or ascites and often form multilayer spheroid-like structures which could attach to mesothelium, invade the peritoneum and initiate metastatic tumor growth (Naora et al.

, 2005; Shield et al., 2009). These spheroids in ascites are capable of tumorigenesis in vivo and are chemoresistant in vitro (Burleson et al., 2006; L'Espérance et al., 2008).

Galectin-3 (Gal-3) is a unique member of galectin family containing a C-terminal carbohydrate recognition domain, which binds to β-galactosides and its N-terminal domain is needed for Gal-3 enigmatic behavior and cross-linking activity (Nio-Kobayashi, 2017 ). Changes in Gal-3 expression are commonly seen in cancer and pre-cancerous conditions (Wang & Guo, 2016). Moreover, Gal-3 has anti- or pro-apoptotic action depending on its subcellular localization and is involved in cellular proliferation, adhesion, motility, metastasis and thereupon tumor progression (Wang & Guo, 2016).

Previous studies associated Gal-3 expression with OC chemoresistance (Kim et al., 2011, Mirandola et al., 2014). PectaSol-C Modified Citrus Pectin (Pect-MCP) is a derivative of pectin which is a soluble dietary supplement with the ability to act as a ligand for Gal-3 due to its high content in b-galactoside residues and impedes Gal-3 interaction with its natural ligands (Campo et al., 2016). Pect-MCP is derived from water-insoluble citrus pectin by PH/temperature-modification (Campo et al., 2016).

In normal cells, Signal transducer and activator of transcription 3 (STAT3) are transiently activated in response to specific growth factors and cytokines, while STAT3 is constitutively activated in many cancerous cells, including OC cells (Sansone et al., 2012; Rosen et al., 2006). STAT3 activation is responsible for several key factors in tumor progression, involving uncontrolled cell proliferation, angiogenesis promotion and importantly facilitating chemoresistance (Groner et al., 2008). In most of the high-grade serous OC, activated phosphorylated STAT3tyr705 (pSTAT3tyr705) was localized in the nucleus and was associated with increased chemoresistance and subsequent decreased patient survival (Colomiere et al., 2009). In addition, the sustained activation of the STAT3 pathway was demonstrated in cisplatin-or paclitaxel-treated OC cell lines (Duan et al., 2006).

Although OC initially responds well to the first-line chemotherapeutic agent Paclitaxel (PTX), it often relapses, and cancer cells become resistant to PTX (Komarova & Bolande, 2013). Concurrent use of two or more anti-cancer drugs provides an efficient approach by affecting distinct molecular targets and minimize drug resistance, toxicity, and side effects but only if the components of the drug combination have a different mechanism of action (Bukowska et al., 2015; Chou et al., 2010).

Multicellular tumor spheroid culture (MCTS) has been reported to be a more suitable candidate for studying drug penetration due to the high resemblance to solid tumors (Hirschhaeuser et al., 2010; Shield et al., 2009). Here we sought to investigate the role of Gal-3 in migration, invasion, and chemoresistance of SKOV3 MCTS and to understand its molecular mechanism. We further explored a possible synergistic effect of Pect-MCP as a specific Gal-3 competitive inhibitor in combination with paclitaxel (PTX) to kill ovarian cancer cell MCTS.