Effect of Rosmarinic Acid on Cell Proliferation, Oxidative Stress, and Apoptosis Pathways in an Animal Model of Induced Glioblastoma Multiforme.

ABSTRACT

BACKGROUND: In brain tumors, the complexity of the pathophysiological processes such as oxidative stress, cell proliferation, angiogenesis, and apoptosis have seriously challenged the definitive treatment. Rosmarinic acid (RA), as a polyphenolic compound, has been found to prevent tumor progression in some aggressive cancers. This study was designed to evaluate the anticancer effects of RA on brain tumors. METHOD: Rats were divided into six groups. Implantation of C6 glioma cells was carried out in the caudate nucleus of the right hemisphere. RA at doses of 5, 10, and 20 mg/kg (i.p.) was administered to the treatment groups for seven days. Tumor volume (by MRI imaging), locomotor ability, survival time, histological alterations (by H & E staining), expression of p53 and p21 mRNAs (by RT-PCR), activities of antioxidant enzymes (superoxide dismutase [SOD] and catalase [CAT] by assay kits), expression of caspase-3 and VEGF (by immunohistochemical analysis), and TUNEL-positive cells (by tunnel staining) were analyzed. RESULTS: The results indicated that the RA at a dose of 20 mg/kg reduced the tumor volume, prolonged survival time, increased p53 and p21 mRNAs, attenuated SOD and CAT activities in tumor tissue, elevated caspase-3, and increased the number of TUNEL-positive cells. Furthermore, histological analysis revealed less invasion of tumor cells into the normal parenchyma in rats treated with RA (20 mg/kg). CONCLUSION: These findings provide evidence that the ability of RA to reduce tumor volume could be related to factors that modulate oxidative stress (SOD and CAT enzymes), cell proliferation (p53 and p21), and apoptosis (caspase-3).