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.

Tenofovir alone or combined with doxorubicin abrogates DMBA-induced mammary cell carcinoma: An insight into its modulatory impact on oxidative/Notch/apoptotic signaling.

AIMS: Breast cancer incidence keeps on growing and emerging as one of the major global challenges, therefore, the introduction of new approaches is of great demand. Drug repurposing is crucial to faster and cheaper discovery of anti-cancer drugs. The antiviral tenofovir disproxil fumarate (TF) was reported to decrease hepatocellular carcinoma risk by interfering with cell cycle and proliferation. This study aimed to scrutinize the role of TF alone or combined with doxorubicin (DOX) in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinoma rat model. MATERIALS AND METHODS: Breast carcinoma was induced by DMBA (7.5 mg/kg, twice/week, subcutaneous into mammary gland) for 4 successive weeks. TF (25 and 50 mg/kg/day) was given orally and DOX (2 mg/kg) was injected once/week by tail vein starting from day 1. KEY FINDINGS: The anti-cancerous effect of TF was mediated by suppression of oxidative stress markers and Notch signaling proteins (Notch1, JAG1, and HES1), attenuation of tumor proliferation markers (cyclin-D1 and Ki67), and boosting of apoptosis (P53 and Caspase3) and autophagy biomarkers (Beclin1 and LC3). In parallel, histopathological assessment displayed that mammary glands from animals treated with TF alone or combined with DOX showed better histopathological scores. Interestingly, TF and DOX co-treatment markedly decreased myocardial injury markers (AST, LDH, and CK-MB), restored the balance between GSH and ROS, prohibited lipid peroxidation, and preserved microscopic myocardial architecture. SIGNIFICANCE: TF elicited antitumor activity via multiple molecular mechanisms. Moreover, combining TF with DOX might be a potential novel strategy to enhance DOX-anticancer activity and decrease its cardiac side effects.

Flavocoxid attenuates airway inflammation in ovalbumin-induced mouse asthma model.

Asthma is a common airways inflammatory disease. This study provides evidence on the efficacy of flavocoxid against ovalbumin (OVA)-induced allergic airways inflammation in a mouse model of asthma. Airway inflammation was induced by intrapеritonеal injection of 10 mg ovalbumin (OVA) on day zero and day 7 followed by OVA challenge starting from 14th day to 16th day. Beclomethasone; a standard anti-inflammatory agent was selected as a drug in asthma. Flavocoxid (20 mg/kg, i. p.) was administered on day zero till 16th day followed by OVA challenge. At the end of the study, lung weight index, bronchoalveolar lavage fluid (BALF) content of total and differential WBCs, interleukin-13(IL-13), in addition to lung tissue nitrate/nitrite (NO) and oxidative stress biomarkers were measured. Also, histological and immunohistochemical analysis were conducted. Daily i. p. injection of flavocoxid (20 mg/kg) significantly improved airway inflammation. Inflammatory cells in BALF, malondialdehyde (MDA), NO and IL-13 significantly declined with concomitant increase in superoxide dismutase (SOD) activity. Histopathological examination and immunohistochеmical staining of mast cells were correlated with observed biochemical improvements. Collectively, these results demonstrate that flavocoxid mitigates the allergic airway inflammation induced by ovalbumin through attenuation of IL-13, NO expressions and oxidative stress.