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The 1,4-naphthoquinones and their derivatives have garnered great interest due to their antitumor pharmacological properties in various cancers; however, their clinical application is limited by side effects. In this study, to reduce side effects and improve therapeutic efficacy, a novel 1,4-naphthoquinone derivative-2-(4-methoxyphenylthio)-5,8-dimethoxy-1,4-naphthoquinone (MPTDMNQ) was synthesized. We investigated the effects and underlying mechanisms of MPTDMNQ on cell viability, apoptosis, and reactive oxygen species (ROS) generation in human gastric cancer cells. Our results showed that MPTDMNQ decreased cell viability in nine human gastric cancer cell lines. MPTDMNQ significantly induced apoptosis accompanied by the accumulation of ROS in GC cells. However, pre-treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) attenuated the MPTDMNQ-induced apoptosis. Moreover, MPTDMNQ decreased the phosphorylation levels of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3); and increased the phosphorylation levels of c-Jun N-terminal kinase (JNK) and p38 kinase. However, phosphorylation was inhibited by NAC and a mitogen-activated protein kinase (MAPK) inhibitor. These findings showed that MPTDMNQ induced AGS cell apoptosis via ROS-mediated MAPK and STAT3 signaling pathways. Thus, MPTDMNQ may be a promising candidate for treating gastric cancer.

1,4-Naphthoquinone compounds are a class of organic compounds derived from naphthalene. They exert a wide variety of biological effects, but when used as anticancer drugs, have varying levels of side effects. In the present study, in order to reduce toxicity and improve the antitumor activity, we synthesized two novel 1,4-naphthoquinone derivatives, 2-(butane-1-sulfinyl)-1,4-naphthoquinone (BSQ) and 2-(octane-1-sulfinyl)-1,4-naphthoquinone (OSQ). We investigated the antitumor effects of BSQ and OSQ in human lung cancer cells and the underlying molecular mechanisms of these effects, focusing on the relationship between these compounds and reactive oxygen species (ROS) production. MTT assay and trypan blue exclusion assay results showed that BSQ and OSQ had significant cytotoxic effects in human lung cancer cells. Flow cytometry results indicated that the number of apoptotic cells and the intracellular ROS levels significantly increased after treatment with BSQ and OSQ. However, cell apoptosis was inhibited by pretreatment with the ROS scavenger N-acetyl-l-cysteine (NAC). Western blotting results showed that BSQ and OSQ increased the expression levels of p-p38 kinase and p-c-Jun N-terminal kinase (p-JNK), and decreased the expression levels of p-extracellular signal-regulated kinase (p-ERK), p-protein kinase B (p-Akt), and p-signal transducer and activator of transcription-3 (p-STAT3). These phenomena were blocked by mitogen-activated protein kinase (MAPK) inhibitors, Akt inhibitors and NAC. In conclusion, BSQ and OSQ induce human lung cancer A549 cell apoptosis by ROS-mediated MAPKs, Akt, and STAT3 signaling pathways. Therefore, BSQ and OSQ may be therapeutic potential agents for the treatment of human lung cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Quinalizarin may be a potential chemical agent for cancer therapy, as it exerts anti‑tumour effects against a variety of different types of cancer. However, the underlying regulatory mechanism and signalling pathways of quinalizarin in lung cancer cells remains unknown. The present study sought to investigate the effects of quinalizarin on proliferation, apoptosis and reactive oxygen species (ROS) generation in lung cancer. MTT assays were used to evaluate the effects of quinalizarin on the viability of lung cancer A549, NCI‑H460 and NCI‑H23 cells. Flow cytometry was employed to evaluate the effects of quinalizarin on the cell cycle, apoptosis and ROS generation in A549 cells. Western blotting was performed to detect cell cycle and apoptosis‑associated protein expression levels in A549 cells. Quinalizarin inhibited A549, NCI‑H460 and NCI‑H23 cell proliferation and induced A549 cell cycle arrest at the G0/G1 phase. Quinalizarin induced apoptosis by upregulating the expression of B‑cell lymphoma 2 (Bcl‑2)‑associated agonist of cell death, cleaved‑caspase‑3 and cleaved‑poly (adenosine diphosphate‑ribose) polymerase, and downregulating the expression of Bcl‑2. Furthermore, quinalizarin activated mitogen‑activated protein kinase (MAPK) and p53, and inhibited the protein kinase B and signal transducer and activator of transcription‑3 (STAT3) signalling pathways. In addition, quinalizarin increased ROS generation. The ROS scavenger N‑acetyl‑L‑cysteine restored quinalizarin‑induced cell apoptosis, and inactivated the MAPK and STAT3 signalling pathways. The results of the present study demonstrated that quinalizarin induces G0/G1 phase cell cycle arrest and apoptosis via ROS mediated‑MAPK and STAT3 signalling pathways.

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. [ABSTRACT FROM AUTHOR]

Liquiritin (LIQ), a major constituent of Glycyrrhiza Radix, exhibits various pharmacological activities. In this study, to explore the potential anti-cancer effects and its underlying molecular mechanisms of LIQ in hepatocellular carcinoma (HCC) cells. LIQ significantly decreased viability and induced apoptosis in HepG2 cells by decreasing mitochondrial membrane potential and regulating Bcl-2 family proteins, cytochrome c, cle-caspase-3, and cle-PARP. The cell cycle analysis and western blot analysis revealed that LIQ induced G2/M phase arrest through increased expression of p21 and decreased levels of p27, cyclin B, and CDK1/2. The flow cytometry and western blot analysis also suggested that LIQ promoted the accumulation of ROS in HepG2 cells and up-regulated the phosphorylation expression levels of p38 kinase, c-Jun N-terminal kinase (JNK), and inhibitor of NF-κB (IκB-α); the phosphorylation levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), signal transducer activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) were down-regulated. However, these effects were reversed by N-acetyl-l-cysteine (NAC), MAPK, and AKT inhibitors. The findings demonstrated that LIQ induced cell cycle arrest and apoptosis via the ROS-mediated MAPK/AKT/NF-κB signaling pathway in HepG2 cells, and the LIQ may serve as a potential therapeutic agent for the treatment of human HCC. [ABSTRACT FROM AUTHOR]

Quinalizarin has been demonstrated to exhibit potent antitumor activities in lung cancer and gastric cancer cells, but currently, little is known regarding its anticancer mechanisms in human breast cancer cells. The aim of the present study was to investigate the apoptotic effects of quinalizarin in MCF-7 cells and to analyze its molecular mechanisms. The MTT assay was used to evaluate the viability of human breast cancer cells that had been treated with quinalizarin and 5-fluorouracil. Flow cytometric analyses and western blotting were used to investigate the effects of quinalizarin on apoptosis and cycle arrest in MCF-7 cells with focus on reactive oxygen species (ROS) production. The results demonstrated that quinalizarin exhibited significant cytotoxic effects on human breast cancer cells in a dose-dependent manner. Accompanying ROS, quinalizarin induced MCF-7 cell mitochondrial-associated apoptosis by regulating mitochondrial-associated apoptosis, and caused cell cycle arrest at the G2/M phase in a time-dependent manner. Furthermore, quinalizarin can activate p38 kinase and JNK, and inhibit the extracellular signal-regulated kinase, signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling pathways. These effects were blocked by mitogen-activated protein kinase (MAPK) inhibitor and N-acetyl-L-cysteine. The results from the present study suggested that quinalizarin induced G2/M phase cell cycle arrest and apoptosis in MCF-7 cells through ROS-mediated MAPK, STAT3 and NF-κB signaling pathways. Thus, quinalizarin may be useful for human breast cancer treatment, as well as the treatment of other cancer types. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (ISL), a natural flavonoid isolated from plant licorice, has various pharmacological properties, including anticancer, anti‐inflammatory, and antiviral effects. However, the underlying mechanisms and signaling pathways of ISL in human hepatocellular carcinoma (HCC) cells remain unknown. In this study, we evaluated the effects of ISL on the apoptosis of human HCC cells with a focus on reactive oxygen species (ROS) production. Our results showed that ISL exhibited cytotoxic effects on two human liver cancer cells in a dose‐dependent manner. ISL significantly induced mitochondrial‐related apoptosis and cell cycle arrest at the G2/M phase, which was accompanied by ROS accumulation in HepG2 cells. However, pretreatment with an ROS scavenger, N‐acetyl‐l‐cysteine (NAC), inhibited ISL‐induced apoptosis. In addition, ISL increased the phosphorylation levels of c‐Jun N‐terminal kinase (JNK), p38 kinase and inhibitor of NF‐κB (IκB), and decreased the phosphorylation levels of extracellular signal‐regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), nuclear factor‐kappa B (NF‐κB), these effects were blocked by NAC and mitogen‐activated protein kinase (MAPK) inhibitors. Taken together, the findings of this study indicate that ISL induced HepG2 cell apoptosis via ROS‐mediated MAPK, STAT3, and NF‐κB signaling pathways. Therefore, ISL may be a potential treatment for human HCC, as well as other cancer types. [ABSTRACT FROM AUTHOR]