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Published on: October 6, 2014
Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice
Justin Korfhage1, Mary E Skinner1, Jookta Basu1
1Department of Pathology, University of Michigan, Ann Arbor, USA.
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.
Insights
The diabetes drug canagliflozin unexpectedly worsened intestinal tumors in mice, particularly in females. This suggests complex, sex-specific effects beyond direct cancer cell impact, potentially involving altered glucose absorption and GLP-1.
Area of Science:
- Pharmacology
- Oncology
- Gastroenterology
Background:
- The diabetes drug canagliflozin has shown life-extending properties in male mice.
- Malignant neoplasms are a primary cause of mortality in mice, suggesting potential anti-neoplastic effects of canagliflozin.
- The study investigates canagliflozin's impact on intestinal tumor burden in a specific mouse model.
Purpose of the Study:
- To evaluate the effect of canagliflozin on intestinal adenoma development in the ApcMin/+ mouse model.
- To explore the mechanisms underlying canagliflozin's effects on neoplasia.
- To investigate potential sex differences in canagliflozin's impact on tumor burden.
Main Methods:
- Treatment of ApcMin/+ mice with canagliflozin.
- Assessment of intestinal tumor burden and area.
- Immunohistochemical analysis of neoplastic cells.
- Measurement of postprandial glucagon-like peptide-1 (GLP-1) levels.
Main Results:
- Canagliflozin unexpectedly increased the total area of intestinal adenomas.
- This effect was more pronounced in the distal intestine and in female mice.
- Canagliflozin did not appear to directly inhibit SGLT1/2 in neoplastic cells.
- Increased postprandial GLP-1 levels were observed, linked to delayed glucose absorption.
Conclusions:
- Canagliflozin exacerbates adenoma development in the ApcMin/+ mouse model through cell-non-autonomous mechanisms.
- Altered distribution of intestinal glucose absorption and subsequent GLP-1 level changes may drive this effect.
- Sex differences in GLP-1 responses might contribute to the sexually dimorphic effects of canagliflozin on lifespan and tumor development.
