Abstract 4954: Opposing effects of the NF-kappaB inhibitor thymoquinone in a syngeneic mouse model of ovarian cancer.

Abstract

Abstract Ovarian cancer is the most lethal gynecologic malignancy. Most women are diagnosed with advanced disease characterized by widespread peritoneal carcinomatosis and abdominal ascites. Activation of inflammatory processes via nuclear factor-kappa B (NF-κB) is involved in ovarian cancer progression and linked to chemotherapy resistance. The potential of NF-κB inhibitors to suppress tumor progression and sensitize tumor cells to platinum chemotherapy has led to their successful use in preclinical tumor models. One such inhibitor is thymoquinone (TQ), a component of black seed oil, widely used in traditional medicine. However, most NF-κB inhibitors including bortezomib have had disappointing clinical results in the treatment of solid tumors. It is possible that NF-κB inhibition in inflammatory cells such as macrophages in the peritoneal cavity may underlie the relatively poor efficacy and toxicity observed in patients. Therefore, this study aimed to determine the effects of TQ on ovarian cancer progression in the immunocompetent host. ID8 mouse ovarian cancer cells expressing the NF-κB-dependent GFP/luciferase (NGL) fusion reporter transgene (ID8-NGL) were injected intraperitoneally (IP) into C57BL/6 mice. Reporter activity was visualized by bioluminescence imaging. TQ or PBS vehicle (VEH) were injected IP thrice weekly from day 30-60 after tumor cell injection. Mice were then sacrificed, ascites collected and tumors harvested. In vitro studies confirmed that TQ inhibited NF-κB activity in ID8-NGL cells, inhibited cell growth, and exerted co-operative inhibitory effects with cisplatin on cell growth. Consistent with the observed in vitro growth inhibition, TQ induced approximately 30% reduction in tumor cells expressing the proliferation marker Ki67 compared to VEH tumors in vivo. However, there was no overall difference in tumor burden (peritoneal and mesenteric tumor nodules). Strikingly, the volume of ascites collected from TQ mice was 5-fold higher than VEH mice, and cytospin analysis of ascites showed that TQ induced a 4-fold increase in the number of macrophages, suggesting an elevated inflammatory response. TQ also increased NF-κB reporter activity by 50% compared to levels in VEH mice. These data suggest that TQ exerts both anti- and pro-tumorigenic effects, likely mediated through NF-κB inhibition in tumor cells and host inflammatory cells, respectively. However, the net effect of treatment is deleterious (increased ascites). These results caution that treating ovarian cancer patients with systemic NF-κB inhibitors may have unanticipated adverse effects, and that a greater understanding of the effects of NF-κB inhibition is necessary before performing combination studies with platinum agents such as cisplatin. Citation Format: Andrew J. Wilson, Jeanette Saskowski, Whitney Barham, Lianyi Chen, Dineo Khabele, Fiona Yull. Opposing effects of the NF-kappaB inhibitor thymoquinone in a syngeneic mouse model of ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4954. doi:10.1158/1538-7445.AM2013-4954