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Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice.

ABSTRACT: The diabetes drug canagliflozin extends life span in male mice. Since malignant neoplasms are the major cause of death in most mouse strains, this observation suggests that canagliflozin might exert anti-neoplastic effects in male mice. Here, we treated a mouse neoplasia model, the adenoma-prone ApcMin/+ strain, with canagliflozin, to test the effects of this drug on intestinal tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect most marked in the distal intestine and in female mice. Immunohistochemical analysis suggested that canagliflozin may not influence adenoma growth via direct SGLT1/2 inhibition in neoplastic cells. Our results are most consistent with a model where canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels driven by delayed glucose absorption. We hypothesize that canagliflozin exacerbates adenomatosis in the ApcMin/+ model via complex, cell-non-autonomous mechanisms, and that sex differences in GLP-1 responses may in part underlie sexually dimorphic effects of this drug on life span.

SUBMITTER: Korfhage J

PROVIDER: S-EPMC8824675 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice.

Korfhage Justin J Skinner Mary E ME Basu Jookta J Greenson Joel K JK Miller Richard A RA Lombard David B DB

The journals of gerontology. Series A, Biological sciences and medical sciences 20220201 2

The diabetes drug canagliflozin extends life span in male mice. Since malignant neoplasms are the major cause of death in most mouse strains, this observation suggests that canagliflozin might exert anti-neoplastic effects in male mice. Here, we treated a mouse neoplasia model, the adenoma-prone ApcMin/+ strain, with canagliflozin, to test the effects of this drug on intestinal tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect most ma ...[more]

PMID: 34448851

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Project description:BACKGROUND:To determine how diets high in saturated fat could increase polyp formation in the mouse model of intestinal neoplasia, ApcMin/+, we conducted large-scale metabolome analysis and association study of colon and small intestine polyp formation from plasma and liver samples of ApcMin/+ vs. wild-type littermates, kept on low vs. high-fat diet. Label-free mass spectrometry was used to quantify untargeted plasma and acyl-CoA liver compounds, respectively. Differences in contrasts of interest were analyzed statistically by unsupervised and supervised modeling approaches, namely Principal Component Analysis and Linear Model of analysis of variance. Correlation between plasma metabolite concentrations and polyp numbers was analyzed with a zero-inflated Generalized Linear Model. RESULTS:Plasma metabolome in parallel to promotion of tumor development comprises a clearly distinct profile in ApcMin/+ mice vs. wild type littermates, which is further altered by high-fat diet. Further, functional metabolomics pathway and network analyses in ApcMin/+ mice on high-fat diet revealed associations between polyp formation and plasma metabolic compounds including those involved in amino-acids metabolism as well as nicotinamide and hippuric acid metabolic pathways. Finally, we also show changes in liver acyl-CoA profiles, which may result from a combination of ApcMin/+-mediated tumor progression and high fat diet. The biological significance of these findings is discussed in the context of intestinal cancer progression. CONCLUSIONS:These studies show that high-throughput metabolomics combined with appropriate statistical modeling and large scale functional approaches can be used to monitor and infer changes and interactions in the metabolome and genome of the host under controlled experimental conditions. Further these studies demonstrate the impact of diet on metabolic pathways and its relation to intestinal cancer progression. Based on our results, metabolic signatures and metabolic pathways of polyposis and intestinal carcinoma have been identified, which may serve as useful targets for the development of therapeutic interventions.

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Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice.

Publications

Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice.

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