Limited tumor growth (HT29) in vivo under RO205-2349 is due to increased apoptosis and reduced cell volume but not to decreased proliferation rate

Abstract 

The peroxisome proliferator-activated receptor (PPARγ) is a nuclear receptor that plays a regulatory role in cell differentiation and proliferation. PPARγ was first detected in adipocytes, however, it has been shown that this receptor is also expressed in normal as well as tumor cells including malignant colonic epithelial cells. In this study, the effect of the PPARγ agonist RO205-2349, a recently developed thiazolidinedione, on tumor growth was evaluated. For this purpose, human colon cancer cells (HT29) were grown in severe combined immunodeficient mice.

Under daily RO205-2349 treatment (50 mg/kg/day) a significantly reduced tumor weight became evident after 3 weeks. In the control (n=10) and treatment (n=10) groups the mean tumor weights were 0.45 and 0.16 g, respectively. The mean percentages of apoptotic cells were 0.8 and 2.7% in the control and treatment groups, respectively, and the cell diameter measured on average 11.4 and 9.4 μm. In contrast, cell proliferation and differentiation, which are considered to be influenced by the PPARγ, remained unaffected as could be seen by Ki-67 and carcinoembryonic antigen immunoreactivity indicating that increased rate of apoptosis and cell shrinkage are responsible for the differences in tumor growth.

Hence, in this human/mouse xenograft model, mechanisms other than the classical activation of PPARγ are likely reasons causing limited tumor growth.

Keywords:  RO205-2349, Colon cancer, Severe combined immunodeficient mice, Peroxisome proliferator-activated receptor gamma, Apoptosis, Cell proliferation