Losartan and Vitamin D Inhibit Colonic Tumor Development in a Conditional Apc-Deleted Mouse Model of Sporadic Colon Cancer

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 þ/LoxP mice and tumor-forming Apc þ/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VDþL, the latter to assess additive or synergistic effects. At 6 months, mice were killed. Plasma Ca 2þ , 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 Creþ VD and Creþ L, but not in the Creþ VDþL group. In Apc þ/LoxP mice, VD increased plasma 1,25 (OH)2D3 and colonic VDR. In Apc þ/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 Creþ 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 Creþ mice, likely contributing to lack of chemopreventive efficacy of the combination.

Clinical Impact of Postoperative Vitamin D Deficiency on the Recurrence of Colon Cancer After Curative Surgical Resection

“…The current study has highlighted the association between vitamin D deficiency and recurrence after curative surgical resection in patients with colon cancer, although it is a (24,25). In addition, supplementation with vitamin D significantly reduced cancer mortality in other studies (30,31).…”

“…A vitamin D deficiency could promote tumorigenesis and the self-renewal of colon cancer stem cells, which may contribute to the relapse of colon cancer after curative resection (23)(24)(25). Wang et al found that vitamin D deficiency impedes the differentiation of colon cancer cells, which supports the maintenance of colon cancer stem cells (26).…”

Adenomatous polyposis coli in cancer and therapeutic implications

“…[95][96][97] One study examined the combination of losartan, an ARB, and/or vitamin D, which is thought to downregulated renin in Apc+/LoxP Cdx2P-Cre mouse models to assess effects on tumor burden. 98 Overall, it appeared that addition of vitamin D and losartan individually decreased tumor burden through upregulation of specific metabolites though the combination of vitamin D and losartan was not significant. 98…”

“… 98 Overall, it appeared that addition of vitamin D and losartan individually decreased tumor burden through upregulation of specific metabolites though the combination of vitamin D and losartan was not significant. 98 …”

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

“…Inhibition of CAF-mediated collagen secretion and cross-linking represents another avenue of active research. Losartan is an indirect inhibitor of Type I collagen synthesis and has shown efficacy in preclinical models of colorectal cancer [204], ovarian cancer [205], breast cancer [206], and lung cancer [206]. A phase II trial of losartan administered with FOLFIRINOX and radiation in the neoadjuvant setting downstaged locally advanced PDACs in 61% of cases [207].…”