2-(Naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone induces apoptosis via ROS-mediated MAPK, AKT, and STAT3
Yang Liu1, Ying-Hua Luo2, Shu-Mei Li3
1Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, China.
Abstract:
1,4-naphthoquinone and its derivatives have attracted widespread attention due to their multiple biological activities, such as induction of cancer cell apoptosis; however, most of these compounds have high cytotoxicity. In this study, in order to reduce their toxicity and increase their potential anti-tumor effects, we synthesized a novel 1,4-naphthoquinone derivative named 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ), and investigated its apoptotic effects and underlying mechanism. Our results showed that NTDMNQ inhibited the viability of HepG2, Hep3B, and Huh7 human hepatocellular carcinoma (HCC) cells. It also increased the accumulation of cells in the G0/G1 phase of the cell cycle by increasing the expression levels of p-p53, p21 and p27, while decreasing the levels of Cyclin D1, Cyclin E, Cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6. Inhibition of reactive oxygen species (ROS) by the ROS scavenger N-acetyl-L-cysteine (NAC) decreased apoptosis in NTDMNQ-treated cells. Western blot analysis showed that NTDMNQ increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and signal transducer and activator of transcription-3 (STAT3); these effects were blocked by NAC. Both the JNK inhibitor (SP600125) and p38 inhibitor (SB203580) reversed the phosphorylation of STAT3, and the ERK inhibitor (FR180204) and AKT inhibitor (LY294002) reduced the expression of STAT3. Taken together, these findings suggest that NTDMNQ induces apoptosis via ROS-mediated MAPK, AKT and STAT3 signaling pathways in HepG2 cells, and may be a potent anticancer agent.
Insights
A novel 1,4-naphthoquinone derivative, NTDMNQ, effectively inhibits hepatocellular carcinoma cell viability. It induces apoptosis through reactive oxygen species-mediated signaling pathways, suggesting potential as an anticancer agent.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- 1,4-naphthoquinone derivatives show anticancer potential but often exhibit high cytotoxicity.
- Developing less toxic derivatives with enhanced anti-tumor effects is crucial for cancer therapy.
Purpose of the Study:
- To synthesize and evaluate a novel 1,4-naphthoquinone derivative, NTDMNQ, for its anti-cancer properties against hepatocellular carcinoma (HCC).
- To elucidate the underlying mechanism of NTDMNQ-induced apoptosis in HCC cells.
Main Methods:
- Synthesis of 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ).
- Assessment of NTDMNQ's effect on HCC cell viability (HepG2, Hep3B, Huh7).
- Cell cycle analysis and Western blot to investigate signaling pathways (MAPK, AKT, STAT3) and reactive oxygen species (ROS) involvement.
Main Results:
- NTDMNQ significantly inhibited the viability of HepG2, Hep3B, and Huh7 HCC cells.
- NTDMNQ induced G0/G1 cell cycle arrest by modulating key cell cycle regulatory proteins.
- Apoptosis induction was dependent on reactive oxygen species (ROS) and involved the modulation of p38, JNK, ERK, AKT, and STAT3 signaling pathways.
Conclusions:
- NTDMNQ demonstrates potent anticancer activity against HCC by inducing apoptosis.
- The mechanism involves ROS generation and subsequent activation of MAPK, AKT, and STAT3 pathways.
- NTDMNQ represents a promising candidate for further development as an anti-HCC therapeutic agent.
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