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Daphnetin ameliorates 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis through Nrf-2-Keap1 and NF-κB
Abhishek Kumar1, S Jha2, Shakti P Pattanayak1
1Division of Pharmacology, Department of Pharm. Sciences & Technology, Birla Institute of Technology, Mesra 835215, Ranchi, Jharkhand, India.
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.
Insights
Daphnetin (DAP) shows promise in preventing mammary cancer by reducing oxidative stress and inflammation. It effectively modulates key pathways like Nrf-2-Keap1 and NF-κB, suggesting its potential as a chemotherapeutic agent.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Oxidative stress and genomic instability are key drivers of mammary carcinogenesis.
- Coumarin derivatives, including daphnetin (DAP), possess anticancer properties.
- The role of DAP in modulating oxidative stress and inflammatory pathways in mammary cancer requires further investigation.
Purpose of the Study:
- To evaluate the antioxidative and chemotherapeutic potential of daphnetin (DAP) in a rat model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis.
- To investigate the effects of DAP on the Keap1-Nrf-2, HO-1, and NF-κB signaling pathways.
- To assess DAP's impact on oxidative stress markers and cell proliferation.
Main Methods:
- Induction of mammary carcinogenesis in female Sprague-Dawley rats using DMBA.
- Administration of DAP to assess its protective effects.
- Measurement of lipid peroxidation, antioxidant enzymes (SOD, CAT, GPx), and glutathione (GSH) levels.
- Analysis of Keap1, Nrf-2, HO-1, and NF-κB mRNA and protein expression.
- Evaluation of p-AKT and p-ERK1/2 signaling pathways.
Main Results:
- DAP demonstrated a protective effect against lipid peroxidation and enhanced antioxidant markers (enzymic and non-enzymic) in serum and tissues.
- DAP treatment led to the upregulation of Nrf-2 and HO-1, with concurrent downregulation of Keap1 and NF-κB.
- DAP inhibited p-AKT, contributing to reduced NF-κB expression, but did not affect p-ERK1/2.
- DAP effectively inhibited mammary carcinogenesis through multiple mechanisms.
Conclusions:
- Daphnetin (DAP) exhibits significant antioxidative and anti-carcinogenic effects against DMBA-induced mammary cancer in rats.
- DAP modulates the Keap1-Nrf-2 pathway and suppresses NF-κB activation, indicating its potential therapeutic value.
- DAP's dual action on these pathways positions it as a promising candidate for mammary cancer management.
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