title: Daphnetin ameliorates 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis through Nrf-2-Keap1 and NF-κB pathways.
abstract: Cancer is a faction of disorders that conjugated primarily with oxidative imbalance. In mammary carcinoma, oxidative stress secondarily changes various gene expressions and signalling pathways that bring genomic instability and mutagenic alterations that fascinating carcinogenesis. Several coumarin compounds are active against various malignancies. Among them, daphnetin (DAP) exhibits valuable safety and bioactivity profile that contributes towards its efficacy against cancer. In this study, the antioxidative and chemotherapeutic potential of DAP against 7,12-dimethylbenz(a)anthracene (DMBA)- induced mammary carcinogenesis was evaluated in female Sprague-Dawley rats. Besides this, we have determined the effect of DAP on Keap1-Nrf-2, associated HO-1 and NF-κB expressions behind the antioxidative and anti-proliferating activity. In our findings, a protective effect of DAP was established against lipid peroxidation, enzymic (Total SOD, MnSOD, CuZnSOD, CAT, GPx) and non-enzymic (GSH) antioxidative markers in serum, liver, kidney and breast tissue of both control and experimental groups. An up-regulation of protective Nrf-2 & HO-1 with a synchronized suppression in Keap1 & NF-κB mRNA and protein expressions were observed. DAP revealed the inhibition of p-AKT which accountable for decrease in NF-κB expressions but shown to be ineffective on p-ERK1/2. This study revealed that DAP inhibits mammary carcinogenesis through multiple mechanisms. Dual efficacy of DAP on Nrf-2-Keap1 pathway and NF-κB expressions propose it as a potential chemotherapeutic agent in mammary cancer management.
authors.affiliation: Division of Pharmacology, Department of Pharm. Sciences & Technology, Birla Institute of Technology, Mesra 835215, Ranchi, Jharkhand, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Pharmacognosy, Department of Pharm. Sciences & Technology, Birla Institute of Technology, Mesra 835215, Ranchi, Jharkhand, India.
authors.forename: S
authors.initials: S
authors.lastname: Jha
authors.affiliation: Division of Pharmacology, Department of Pharm. Sciences & Technology, Birla Institute of Technology, Mesra 835215, Ranchi, Jharkhand, India. Electronic address: sppattanayak@bitmesra.ac.in.
authors.forename: Shakti P
authors.initials: SP
authors.lastname: Pattanayak
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000139:chemically induced* / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014468:Umbelliferones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D014408:Biomarkers, Tumor; D016207:Cytokines; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D009363:Neoplasm Proteins; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D014468:Umbelliferones; D015127:9,10-Dimethyl-1,2-benzanthracene; C039952:daphnetin
keywords: DMBA; Daphnetin; Keap1; Mammary carcinogenesis; NF-κB; Nrf-2