The novel NSAID-derivative, MCI-030, prevents ovarian cancer in the egg-laying hen by increasing tumor cell apoptosis and decreasing beta-catenin and MAPK oncogenic signaling

Abstract

Objectives: The egg-laying hen is an ideal model to study chemoprevention of epithelial ovarian cancer (EOC) as aging hens have a high rate of spontaneous EOC and similar clinicopathological characteristics of the disease to women. Our previous research revealed that the novel non-COX inhibitory NSAID-derivative, MCI-030, decreased ovarian cancer incidence in the hen. MCI-030 inhibits PDE10A, which was shown to be an effective therapeutic target in colon and lung cancers, reducing beta-catenin and MAPK signaling. Molecular analysis of MCI-030 treated hens was performed to study the mechanism by which PDE10A inhibition can reduce ovarian cancer risk. Methods: A total of 225 White leghorn hens aged 2.5 to 3 years old were treated through their feed with MCI-030 or its parent compound, sulindac, for 6- and 12-months and compared to a control group (Figure 1A). Necropsy was performed at each time point to formally assess for tumors with 60 hens evaluated at 6-months and 85 at 12-months. Logistic regression with Firth correction to estimate effect size for this pilot study was performed. Ovary and oviduct tissues were harvested and formalin-fixed or flash-frozen then paraffin-embedded or homogenized, respectively. Molecular analyses were performed using fluorescent immunohistochemistry, TUNEL assays, and western blotting. Results: A trend of decreased risk of malignancy was observed in the MCI-030 group at 6- and 12-months versus control with odds ratios (OR) of 0.56 and 0.75, respectively (95% CI 0.121-2.633, 0.22-2.58). In contrast, this trend was not observed for sulindac (6-month OR=1.56, 95% CI 0.405-6.06, 12-month OR=0.94, 95% CI 0.29-3.03). Assessment of apoptosis in hen ovaries by TUNEL assay demonstrated that MCI-030 significantly increased apoptosis both overall and in ovarian tumors (Figure 1B). Western blotting revealed that pERK was significantly decreased in ovaries of sulindac and MCI-030 hens (Figure 1C). Immunohistochemistry showed that MCI-030 significantly decreased nuclear translocation of beta-catenin and levels of active beta-catenin in ovarian tumors (Figure 1D). Download : Download high-res image (224KB) Download : Download full-size image Conclusions: MCI-030 appears to be a promising agent for the chemoprevention and treatment of ovarian cancer. Molecular analysis of its efficacy in hens revealed that MCI-030 increases tumor apoptosis and decreases pERK and beta-catenin oncogenic signaling. Further investigation of MCI-030 in additional model systems and in-human trials is warranted.