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![Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F60445.jpg&w=3840&q=50)
Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA
Published on: December 19, 2019
Prophylaxis of Diallyl Disulfide on Skin Carcinogenic Model via p21-dependent Nrf2 stabilization
Yunlong Shan1, Zhonghong Wei1, Li Tao1
1Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Abstract:
Cancer prevention through intake of biologically active natural products appears to be an accessible way to reduce the risk of cancer. Diallyl disulfide (DADS), a major garlic derivative, has exhibited potential role in cancer therapy. The study is aimed to evaluate the prophylactic effect of DADS in chemically induced mouse skin carcinogenesis and investigate the molecular targets mediated by DADS. Two-stage chemically induced carcinogenesis model by cutaneous application of DMBA and subsequent TPA was established to study the prophylactic effect of DADS. As a result, we observed that DADS dose-dependently attenuated skin tumor incidence and multiplicity in the model mice, which was related to the up-regulation of a bunch of antioxidant enzymes activities and the nuclear accumulation of Nrf2. Furthermore, we developed skin carcinogenesis in Nrf2 knockout mice which could reverse the activity of DADS. Finally, we uncovered the underlying mechanism that DADS promoted the endogenous interaction between p21 and Nrf2, which was critical for impairing the Keap1-mediated degradation of Nrf2. Based on the results, we concluded that DADS was a promising cancer chemoprevention agent and suggested a garlic-rich diet might be beneficial to reduce the cancer risk in our daily life.
Insights
Diallyl disulfide (DADS), a garlic compound, shows promise in preventing skin cancer by boosting antioxidant defenses and Nrf2 activity. This natural product may reduce cancer risk, highlighting the benefits of a garlic-rich diet.
Area of Science:
- Oncology
- Natural Products Chemistry
- Molecular Biology
Background:
- Chemoprevention using natural products offers an accessible strategy for cancer risk reduction.
- Diallyl disulfide (DADS), a key compound in garlic, demonstrates potential in cancer therapy.
Purpose of the Study:
- To evaluate the prophylactic effects of DADS against chemically induced skin carcinogenesis in mice.
- To investigate the molecular mechanisms and targets through which DADS exerts its chemopreventive effects.
Main Methods:
- A two-stage mouse skin carcinogenesis model was established using DMBA and TPA.
- DADS's efficacy was assessed in both wild-type and Nrf2 knockout mice.
- Molecular targets, including antioxidant enzymes, Nrf2, p21, and Keap1, were investigated.
Main Results:
- DADS significantly reduced skin tumor incidence and multiplicity in a dose-dependent manner.
- DADS treatment led to increased antioxidant enzyme activity and nuclear accumulation of Nrf2.
- The protective effect of DADS was diminished in Nrf2 knockout mice.
- DADS was found to enhance the interaction between p21 and Nrf2, inhibiting Keap1-mediated Nrf2 degradation.
Conclusions:
- Diallyl disulfide (DADS) is a potent chemopreventive agent against skin carcinogenesis.
- DADS functions by upregulating antioxidant enzymes and Nrf2 activity, partly through enhancing p21-Nrf2 interaction.
- A diet rich in garlic may contribute to cancer risk reduction.
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