The high affinity peroxisome proliferator‐activated receptor‐gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane‐treated mice

Abstract

We evaluated RS5444, a thiazolidinedione high affinity PPARγ agonist, for the ability to inhibit colon carcinogenesis in azoxymethane (AOM)-treated mice. In our initial experiment, mice were treated with RS5444 during AOM treatment, and the drug was withdrawn 12 weeks after the last injection of AOM. RS5444 significantly inhibited aberrant crypt focus formation under these circumstances. Furthermore, exposure to RS5444 during the course of AOM treatment effectively blocked colon tumor formation after withdrawal of the agonist. PPARγ expression and nuclear localization were reduced in adenomas. RS5444 did not inhibit DNA synthesis in tumor cells, suggesting that PPARγ activity was impaired in adenomas. To test this hypothesis, pre-existing adenomas were treated with RS5444 for 16 weeks. We observed a slight, albeit not statistically significant, reduction in tumor incidence in RS5444-treated mice. However, histological examination revealed that tumors from RS5444-treated mice were of significantly lower grade, as evaluated by the extent of dysplasia. Furthermore, carcinoma in situ was observed in about one-third of control tumors, but was never observed in RS5444-treated tumors. We conclude that RS5444 inhibits both initiation and progression of colon tumors in the AOM model of sporadic colon carcinogenesis.

Functional characterization of peroxisome proliferator‐activated receptor‐β/δ expression in colon cancer

“…Similar results have also been observed in small intestine polyps from Apc +/Min mice [19]. Additionally, decreased PPARγ mRNA was also reported to occur in colon polyps from azoxymethane‐treated mice that correlated with reduced protein expression based on immunohistochemical analysis [36]. In contrast, other studies reported no change in expression of PPARγ in Apc +/Min mice [37, 38] or even increased expression of PPARγ in colon polyps from azoxymethane‐treated rats or Apc +/Min mice [39–41].…”

2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications

“…In a 6-year population-based cohort study, thiazolidinediones were associated with decreased cancer risk including CRC and the association was dose-dependent [ 231 ]. Thiazolidinediones have cytostatic effects and inhibit growth and metastasis of colon cancer cells as they induce differentiation and modulate the E-cadherin/β-catenin system [ 232 – 234 ]. However, some studies point to a mitogenic potential of troglitazone which induced colon tumors in normal C57BL/6J mice and increased colon carcinogenesis in Apc1638 N/+Mlh1 +/− double mutant mice [ 235 ].…”

Antihyperglycaemic therapies and cancer risk

“…Numerous studies pointed to a tumour suppressor effect of the TZDs reporting an impact on angiogenesis, inhibition of cell differentiation and invasion, cell cycle arrest and induction of apoptosis. [70][71][72][73][74][75][76][77][78][79][80] Of note, this antimitogenic effect of TZDs may be independent of PPARγ itself, raising the need for further investigations regarding accurate molecular mechanisms. 81 In the meantime, several clinical trials are available linking TZD treatment to cancer incidence and survival in humans, although, also in this regard, conflicting results are reported with regard to site-specific cancers and differences between different representatives of this drug class.…”