Tiron enhances the anti-cancer activity of doxorubicin in DMBA-induced breast cancer: Role of Notch signaling/apoptosis/autophagy/oxidative stress

Existing work intended to investigate the outcomes of the localized mitochondrial antioxidant tiron (TR) alone or in combination with doxorubicin (DOX) in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in rats and the mechanistic pathways behind these effects. Also, to examine the preventive role of TR against DOX-related cardiotoxicity. 64 female Sprague-Dawley rats were randomly assigned into 8 groups: CTRL, DOX, TR, DMBA, DMBA + DOX, DMBA + TR100, DMBA + TR200, and DMBA + DOX + TR200. Rats received TR (100 and 200 mg/kg), DOX (2mg/kg), and DMBA (7.5 mg/kg) for four consecutive weeks. TR alone or combined with DOX not only inhibited oxidative status-related parameters and Notch pathway proteins but also attenuated proliferation markers, and enhanced apoptosis, and autophagy-related genes. Consistently, the histopathological analysis showed better scores in mammary tissues isolated from groups treated with TR only or combined with DOX. Additionally, TR dramatically decreased relative heart weight, myocardial injury biomarkers, and heart oxidative stress parameters while maintaining the myocardial histological integrity. Here we provided evidence that TR acts via modulating Notch signaling/apoptosis/autophagy/oxidative stress to elicit anti-tumor activity and combination with DOX revealed a higher efficacy as a novel anticancer strategy. Moreover, TR could be a potential cardio-protective candidate during DOX-chemotherapy, possibly via its antioxidant activity. The proposed antitumor mechanism of tiron (TR, 100 and 200 mg/kg, intraperitoneal) against 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinoma.4-HNE; 4-hydroxynonenal, AST; aspartate transaminase enzyme, CK-MB; creatine kinase-myoglobin binding, DMBA: 7,12-dimethylbenz[a]anthracene, DOX: doxorubicin, GSH: reduced glutathione, HES1: hairy and enhancer of Split 1, I.V: intravenous, JAG1; protein jagged-1, LC3; microtubule associated protein 1 light chain3, LDH; lactate dehydrogenase enzyme, MDA; malondialdehyde, NEXT: notch extracellular truncation, NICD: notch intracellular domain, P53; tumor protein P53, ROS; reactive oxygen species, S.C: subcutaneous, TR; tiron. [Display omitted]