Novel 1,4‑naphthoquinone derivatives induce reactive oxygen species‑mediated apoptosis in liver cancer cells

Abstract

Derivatives of 1,4-naphthoquinone have excellent anti-cancer effects, but their use has been greatly limited due to their serious side effects. To develop compounds with decreased side effects and improved anti-cancer activity, two novel types of 1,4-naphthoquinone derivatives, 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ) were synthesized and their anti-tumor activities were investigated. The effects of EPDMNQ and ENDMNQ on cell viability, apoptosis and accumulation of reactive oxygen species (ROS) in liver cancer cells were determined by MTT cell viability assay and flow cytometry. The expression levels of mitochondrial, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathway-associated proteins in Hep3B liver cancer cells were analyzed by western blot analysis. The results demonstrated that EPDMNQ and ENDMNQ inhibited the proliferation of liver cancer Hep3B, HepG2, and Huh7 cell lines but not that of normal liver L-02, normal lung IMR-90 and stomach GES-1 cell lines. The number of apoptotic cells and ROS levels were significantly increased following treatment with EPDMNQ and ENDMNQ, and these effects were blocked by the ROS inhibitor N -acetyl-L-cysteine (NAC) in Hep3B cells. EPDMNQ and ENDMNQ induced apoptosis by upregulating the protein expression of p38 MAPK and c-Jun N-terminal kinase and downregulating extracellular signal-regulated kinase and STAT3; these effects were inhibited by NAC. The results of the present study demonstrated that EPDMNQ and ENDMNQ induced apoptosis through ROS-modulated MAPK and STAT3 signaling pathways in Hep3B cells. Therefore, these novel 1,4-naphthoquinone derivatives may be useful as anticancer agents for the treatment of liver cancer.

Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX-2

“…Cancerous cell invasion and hematogenous and lymphatic dissemination is the first and the most crucial step in metastatic cascade leading to multiorgan involvement [ 42 , 43 , 44 ]. Transformed cells acquire the ability to leave the primary tumor location; migrate to and penetrate the surrounding tissues, lymphatic, and blood vessels; and disseminate [ 42 , 43 , 44 ]. Therefore, the pharmacological inhibition of cancerous cell migration could potentially prevent metastatic events.…”

1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line

“…In the current study, CNN1 caused depolarization of mitochondrial membrane potential in both leukemia cell lines and was more pronounced when compared to IM ( p < 0.001). Previous studies have reported a decrease in mitochondrial membrane potential induced by 1,4-naphthoquinone in liver cancer cells (Hep3B), leukemia cells (HL-60), and human breast adenocarcinoma cells (MCF-7) [ 26 , 43 , 44 ]. The deregulation of apoptotic pathways induces leukemic cells to accumulate, thus promoting further genetic alterations and also the leukemogenesis, therefore, mitochondrial damage may be a promising strategy in the regulation of apoptosis in CML [ 45 ].…”

Cytisine exerts anti-tumour effects on lung cancer cells by modulating reactive oxygen species-mediated signalling pathways

“…In subsequent experiments, we paid further attention to the apoptosis and underlying cell cycle arrest mechanisms. MAPKs are a large family of seine/threonine kinases that mediate cellular signals [22]. ERK is usually associated with Figure 5.…”