Losartan and Vitamin D Inhibit Colonic Tumor Development in a Conditional Apc-Deleted Mouse Model of Sporadic Colon Cancer
©2019 American Association for Cancer Research..
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 6 months, mice were killed. Plasma Ca2+, 25(OH)D3, 1α, 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 Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Cancer prevention research (Philadelphia, Pa.) - 12(2019), 7 vom: 01. Juli, Seite 433-448 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dougherty, Urszula [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.08.2020 Date Revised 28.08.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/1940-6207.CAPR-18-0380 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 245 | 1 | 0 | |a Losartan and Vitamin D Inhibit Colonic Tumor Development in a Conditional Apc-Deleted Mouse Model of Sporadic Colon Cancer |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Revised 28.08.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2019 American Association for Cancer Research. | ||
| 520 | |a 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 6 months, mice were killed. Plasma Ca2+, 25(OH)D3, 1α, 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 Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Adenomatous Polyposis Coli Protein |2 NLM | |
| 650 | 7 | |a Angiotensin II Type 1 Receptor Blockers |2 NLM | |
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| 700 | 1 | |a Haider, Haider I |e verfasserin |4 aut | |
| 700 | 1 | |a Khalil, Abdurahman |e verfasserin |4 aut | |
| 700 | 1 | |a Souris, Jeffrey S |e verfasserin |4 aut | |
| 700 | 1 | |a Joseph, Loren |e verfasserin |4 aut | |
| 700 | 1 | |a Hart, John |e verfasserin |4 aut | |
| 700 | 1 | |a Konda, Vani J |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Pekow, Joel |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yan Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Bissonnette, Marc |e verfasserin |4 aut | |
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