Simultaneous Administration of Statins and Pioglitazone Limits Tumor Growth in a Rat Model of Malignant Glioma.

ABSTRACT

BACKGROUND/AIM: Statins are cholesterol reducers with considerable dose-dependent effect against glioma cells. The apoptotic effect could be increased by combining statins or by adding pioglitazone (PGZ). The last one is an anti-diabetic drug, an agonist of the peroxisome proliferator-activated receptor-gamma (PPARG). We used an animal model to test the effect of such combination in vivo and we investigated the changes on immunological processes. MATERIALS AND METHODS: Thirty-three rats (F344/DuCrl) were anesthetized and glioblastoma (F98) cells were implanted stereotactically. Animals were randomized into four groups i) control (N=9); ii) intraperitoneal injection of PGZ 10 mg/kg/day (N=8); iii) oral administration of atorvastatin (ATVS) 40 mg/kg and lovastatin (LVS) 50 mg/kg (N=8); iv) oral administration of ATVS 40 mg/kg, LVS 50 mg/kg and PGZ 5 mg/kg (N=8). Treatment was started at 3rd postoperative day and continued for 14 days. The animals were followed-up for 30 days after start of therapy. Survival time, tumor volume, proliferation rate, counts of peripheral and tumor infiltrating leukocytes were compared. RESULTS: No difference of survival time or incidence of neurological deficits was observed. The combination of statins with PGZ led to a significant reduction in tumor volume by approximately 40% (p<0.05), statins combination was less effective and PGZ alone did not affect tumor volume. The groups treated with statins displayed significantly lower counts of peripheral CD3+, CD4+ and CD8+ T-cells and lower tumor associated CD68-positive cells (p<0.01, in respect to controls or PGZ alone). The proliferation rate was not statistically different. No relevant toxic effects were observed. DISCUSSION: Statins and PGZ are well-tolerated in rats and produced a significant tumor reduction, while an impact on neurological deficits or survival improvement could not be demonstrated. The reduction of infiltrating macrophages by using statins and PGZ should be further studied.