Losartan and vitamin D inhibit colonic tumor development in a conditional Apc-deleted mouse model of sporadic colon cancer
Menée sur un modèle murin de cancer sporadique du côlon avec délétion du gène APC, cette étude met en évidence l'intérêt de la vitamine D et du losartan, un antagoniste des récepteurs de l'angiotensine II, pour inhiber la carcinogenèse
Colorectal cancer (CRC) is a leading cause of cancer-deaths. The renin-angiotensin system (RAS) is up-regulated in CRC and epidemiological studies suggest RAS inhibitors reduce cancer risk. Since vitamin D receptor negatively regulates renin, we examined anti-cancer efficacy of vitamin D (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 vitamin D (VD), losartan (L) or VD+L, the latter to assess additive or synergistic effects. At 6-mo mice were killed. Plasma Ca2+, 25(OH)D3, 1α,25 (OH)2D3, renin and 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 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 down-regulated. Losartan 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 Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.
Cancer Prevention Research , résumé, 2018