Investigation of the therapeutic effect of parthenolide on heart toxicity in rats caused by paclitaxel frequently used in chemotherapy

In this thesis, it is aimed to investigate the therapeutic effects of parthenolide (PTL), an active component of Feverfew (Tanacetum parthenium) L., on the cardiotoxicity induced by paclitaxel (PTX), a widely used anticancer drug in various cancer treatments, at the gene and protein levels. For this purpose, 48 male rats (Sprague-Dawley) were divided into 6 groups with 8 animals in each group. The 1st group was the control group, and no intervention was made on the animals in this group. The 2nd group received a cumulative dose of 8 mg/kg PTX. The 3rd group, called the sham group, received DMSO, which is the solvent of PTL evaluated for its therapeutic effect. The 4th, 5th, and 6th groups were the treatment groups. These groups received a single dose of 8 mg/kg PTX and subsequently underwent a 14-day treatment with 1 mg/kg PTL, 2 mg/kg PTL, and 4 mg/kg PTL, respectively. After the last PTL dose, the rats were sacrificed, and the quantitative amounts of the antioxidant metabolite reduced glutathione (GSH) and the lipid peroxidation marker malondialdehyde (MDA) in the heart tissues were examined spectrophotometrically. Additionally, changes in the levels of the DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG), and inflammation markers inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) proteins were determined by immunohistochemical analysis. Hematoxylin-eosin (H&E) staining was also performed to investigate the effect of PTL in treating cardiac tissue damage induced by PTX, evaluating hemorrhage and mononuclear cell infiltration changes in the heart tissues. The enzyme activity and gene expression levels of antioxidant system components superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), and glutathione reductase (GR) were measured and compared among the groups. The data obtained from the study indicate that the values of antioxidant system components GSH and MDA changed in the direction of oxidative damage with PTX and returned to normal levels with PTL treatment. Pathological evaluation revealed that hemorrhage and mononuclear cell infiltration caused by PTX showed improvement with PTL. Additionally, the DNA damage marker 8-OHdG and the inflammation markers iNOS and COX-2 approached normal levels with PTL treatment. Furthermore, when antioxidant enzymes were examined at the gene and protein levels, it was observed that parthenolide exhibited a significantly high therapeutic effect against paclitaxel-induced cardiotoxicity. Keywords: Parthenolide, Cancer, Cardiotoxicity, Paclitaxel, Expression, Antioxidant System, Enzyme Activity