Abstract 2721: Growth of HCT-116 colon cancer xenografts is inhibited by CysLT1R antagonists.

Abstract

Abstract Background Cysteinyl leukotrienes (LTC4, LTD4 and LTE4) are potent pro-inflammatory molecules derived from arachidonic acid and mediate their effect through CysLT1R and CysLT2R. There is a strong correlation between long-standing inflammatory bowel disease where these pro-inflammatory mediators are abundant and colorectal cancer. We have shown that LTD4 via its receptor CysLT1 induces up-regulation of colon cancer associated proteins (COX-2, β-catenin and Bcl-2) and induces cell migration and cell survival. In addition, our previous work has shown that CysLT1R is upregulated in colon cancer patients and associated with poor prognosis. Aim and Methods The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 μM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued daily treatment (5 mg/kg, i.p.). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor initiation. Furthermore, we performed a series of in vitro studies using the human colon cancer cell line HCT-116 and CysLT1R antagonists. Results In the HCT-116 colon cancer xenograft model both drug administration regimens resulted in significantly reduced tumor size, attributed to increased levels of p21WAF/Cip1 (P < 0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P < 0.01) and reduced vessel size (P < 0.05) were also observed, the latter only in the ZM198,615-pretreatment group. When administrating CysLT1R antagonists in vitro, a significant reduction in cell proliferation, adhesion and colony formation were observed for the HCT-116 cell line. In addition, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. Conclusion Our results demonstrate that CysLT1R antagonists inhibit tumor growth in a xenograft model of colon cancer by impairing angiogenesis and inducing apoptosis. The present in vivo data also highlight the prospect of this receptor in targeted colon cancer therapy. Grant acknowledgements This work was supported by grants awarded to the authors A. Sjölander from the Swedish Cancer Foundation, the Swedish Medical Research Council. Citation Format: Anita Sjölander, Sayeh Savari, Yuan Zhang, Wondossen Sime, Naveen Kumar Chandrashekar, Minghui Liu. Growth of HCT-116 colon cancer xenografts is inhibited by CysLT1R antagonists. [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 2721. doi:10.1158/1538-7445.AM2013-2721