Montelukast, a CysLT1 receptor antagonist, reduces colon cancer stemness and tumor burden in a mouse xenograft model of human colon cancer. (28th November 2018)

• Record Type: Journal Article
• Authors: Bellamkonda, Kishan; Satapathy, Shakti Ranjan; Douglas, Desiree; Chandrashekar, Naveenkumar; Selvanesan, Benson Chellakkan; Liu, Minghui; Savari, Sayeh; Jonsson, Gunilla; Sjölander, Anita
• Is Part Of: Cancer letters. Volume 437(2018)
• Page Start: 13
• Page End: 24
• Publication Date: 2018-11-28
• Subjects: Colon cancer -- CysLT1 receptor -- Montelukast -- Colon cancer stem cells -- ALDH1 -- DCLK1; ALDH Aldehyde dehydrogenase -- CC Colon cancer -- CRC Colorectal cancer -- CSCs Cancer stem cells -- CICs Cancer initiating cells -- COX-2 Cyclooxygenase 2 -- LTD4 Leukotriene D4 -- Mo Montelukast -- CysLT1R cysteinyl leukotriene receptor 1 -- CysLT2R cysteinyl leukotriene receptor 2 -- IL-4 interleukin-4; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.08.019
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Inflammation is implicated in the etiology of sporadic colon cancer (CC), which is one of the leading causes of cancer-related deaths worldwide. Here, we report that inhibition of the inflammatory receptor CysLT1 through its antagonist, montelukast, is beneficial in minimizing stemness in CC and thereby minimizing tumor growth in a mouse xenograft model of human colon cancer. Upon treatment with montelukast, colonospheres derived from HT-29 and SW-480 human colon cancer cells exhibited a significant phenotypic change coupled with the downregulation of mRNA and protein expression of cancer stem cell (CSC) markers ALDH1 and DCLK1. Moreover, montelukast reduced the size of HT-29 cell-derived tumors in mice. The reduction in tumor size was associated with decreased levels of ALDH1A1, DCLK1, BCL2 mRNA and macrophage infiltration into the tumor tissue. Interestingly, this treatment elevated levels of the tumor suppressor 15-PGDH while reducing COX-2 expression. Our data highlight the association of CysLT1 R with CSCs and demonstrate that inhibition of CysLT1 R could prove beneficial in minimizing CSC-induced tumor growth. This work advances the notion that targeting CSCs is a promising approach to improve outcomes in those afflicted with colon cancer. Highlights: The CysLT1 receptor antagonist Montelukast decreased the colony forming ability of colon cancer cells. Montelukast also reduces the number of colon cancer stem cells identified by the colon cancer stem cell marker DCLK1 in colonospheres. In vivo treatment with Montelukast reduced the size of human colon cancer tumor in a mouse xenograft model. These effects of Montelukast are supported by increased 15-PGDH and decreased COX-2 expression in colon cancer cells both in vitro and in vivo.