Losartan and Vitamin D inhibit colonic tumor development in a conditional apc-deleted mouse model of sporadic colon cancer

Urszula Dougherty, Reba Mustafi, Haider I. Haider, Abdurahman Khalil, Jeffrey S. Souris, Loren Joseph, John Hart, Vani J. Konda, Wei Zhang, Joel Pekow, Yan Chun Li, Marc Bissonnette*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because Vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc+/LoxP mice and tumor-forming Apc+/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6months, mice were killed. Plasma Ca2+, 25(OH)D3, 1a, 25(OH) 2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc+/LoxP mice, VD increased plasma 1,25 (OH)2D3 and colonic VDR. In Apc+/LoxP-Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cremice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.

Original languageEnglish (US)
Pages (from-to)433-448
Number of pages16
JournalCancer Prevention Research
Volume12
Issue number7
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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