Adrenocortical carcinoma (ACC) is a rare and aggressive tumour with a poor prognosis, characterized by radio/chemotherapy resistance. The lack of an effective medical treatment is due to the poor knowledge of the mechanisms underlying malignant tumour transformation and aggressiveness. In vitro studies on the ACC H295R cell model have demonstrated that RGZ, an antidiabetic drug belonging to the thiazolidinedione ligands of PPARgamma, blocks cell proliferation/migration and induce cell differentiation/apoptosis. Moreover, PPARgamma ligands have been shown to inhibit primary tumour and metastasis growth in different cancers.
This study aim at evaluating RGZ effects in a human adrenocortical carcinoma xenograft model. Tumour xenograft was obtained by subcutaneous injection of 7×106 H295R cells in nude Balb/c mice. When the tumour size reached 5 mm, the animals were randomly allocated to 2 groups orally treated with 5 mg/kg RGZ (n=9) or water (n=13), 6 days a week for 31 days. Tumour volume was measured twice a week. At the end of the treatment, mice were sacrificed and tumours were split for histological/immunohistochemical or RT-PCR analyses.
A statistically significant reduction of tumour growth in the RGZ versus control group (P=0.007) was observed. Histological and immunohistochemical evaluation of the tumour revealed characteristics of invasiveness, richness in small vessels and mitotic figures in control group, while RGZ group tumours presented expanding and not infiltrating borders, with few vessel and many apoptotic bodies, and reduction in proliferation. Quantitative real time RT-PCR demonstrated a statistically significant reduction in the expression of angiogenic and vascular (VEGF and CD31), proliferation (BMI1) and anti-apoptotic (Bcl-2) genes as well as in the number of human H295R cells, in RGZ versus control group tumours (P<0.05, Student t-test).
In conclusion, our findings support a role of RGZ in controlling ACC proliferation and angiogenesis. Further investigations are needed to clarify the molecular mechanisms underlying RGZ anticancer effects.
25 - 29 Apr 2009
European Society of Endocrinology