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Unprecedented progress in immune checkpoint blockade (ICB) therapy has been made in cancer treatment. However, the response to ICB therapy is limited to a small subset of patients. The development of ICB sensitizers to improve cancer immunotherapy outcomes is urgently needed. Berberine (BBR), a well-known phytochemical compound isolated from many kinds of medicinal plants such as Berberis aristata, Coptis chinensis, and Phellondendron chinense Schneid, has shown the ability to inhibit the proliferation, invasion and metastasis of cancer cells. In this study, we investigated whether BBR can enhance the therapeutic benefit of ICB for melanoma, and explored the underlying mechanisms involved. The results showed that BBR could sensitize ICB to inhibit tumor growth and increased the survival rate of mice. Moreover, BBR stimulated intracellular ROS production partially by inhibiting NQO1 activity, which induced immunogenic cell death (ICD) in melanoma, elevated the levels of damage-associated molecular patterns (DAMPs), and subsequently activated DC cells and CD8 + T cells in vitro and in vivo. In conclusion, BBR is a novel ICD inducer. BBR could enhance the therapeutic benefit of ICB for melanoma. These effects were partially mediated through the inhibition of NQO1 and ROS activation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

BRAF inhibitors (BRAFi) represent a cornerstone in melanoma therapy due to their high efficacy. However, the emergence of resistance causes a significant challenge to their clinical utility. This study aims to investigate the potential of diclofenac as a sensitizer for BRAFi therapy in melanoma and to elucidate its underlying mechanism. BRAFi-acquired resistant melanoma cell lines SK-MEL-5R and A375R were established and treated with diclofenac in combination with BRAFi PLX4032. Cell viability was assessed using the MTT assay, cell proliferation was determined by crystal violet staining, cell apoptosis was evaluated by flow cytometry, and intracellular ROS levels were measured using the DCFH-DA probe-labeled and flow cytometry. Mitochondrial membrane potential was assessed by JC-1 staining and flow cytometry, and protein expression levels were detected by western blotting. Our results demonstrated that diclofenac significantly augmented the cytotoxicity of PLX4032 and enhanced its ability to induce apoptosis in SK-MEL-5R and A375R cells. Diclofenac treatment led to the release of intracellular reactive oxygen species (ROS), consequently reducing transmembrane potential, promoting mitochondrial apoptosis, and activating the ROS downstream p38/p53 signaling pathway. Pretreatment with N-acetylcysteine significantly reversed the sensitizing effect of diclofenac on PLX4032 in SK-MEL-5R cells. These findings suggested that diclofenac sensitized BRAFi-resistant melanoma cells to BRAFi by increasing ROS release and activating p38/p53 signaling pathway. Diclofenac might serve as a promising adjunct therapy to overcome BRAFi resistance in melanoma treatment., (© 2025 John Wiley & Sons Australia, Ltd.)

Metastatic melanoma is the most aggressive skin cancer. Although BRAF inhibitor treatment has achieved great success in melanoma, resistance develops within 12 months. Icariside II (IS), a natural compound extracted from Herba Epimedii, exerts anticancer properties. In the present study, we determined by MTT, flow cytometry and western blotting, respectively that IS potentiated the PLX4032‑induced downregulation of cell viability and increase in apoptosis and autophagy in BRAF inhibitor‑resistant melanoma. In addition, we also revealed by flow cytometry and western blotting, respectively, that IS combined with PLX4032 increased mitochondrial and intracellular reactive oxygen species (ROS) generation and subsequently promoted depolarization of mitochondria and release of apoptotic proteins. N‑acetyl cysteine (NAC) and glutathione (GSH), ROS scavengers, reversed the IS‑induced enhancement of the response to PLX4032. Microphthalmia‑associated transcription factor (MITF) and tyrosine‑protein kinase Met (c‑Met) are well‑known factors that contribute to BRAF inhibitor resistance. Furthermore, c‑Met is a direct transcriptional target of MITF in melanocytes and melanoma cells. It was also revealed that IS markedly inhibited MITF and c‑Met expression partially by increasing ROS production in BRAF inhibitor‑resistant melanoma cells.

Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL)‑based cancer therapy offers promise as TRAIL can kill cancer cells without apparent toxicity towards normal cells. However, intrinsic or acquired resistance to TRAIL inseveral types of cancer cell has become a major challenge in TRAIL‑based cancer therapy. Juglone is a natural compound isolated from walnut trees. In the present study, it was demonstrated that juglone sensitized melanoma cells to TRAIL‑induced cytotoxicity by MTT and crystal violet assays. Flow cytometry analysis indicated that juglone potentiated TRAIL‑induced cell death. Western blot assay demonstrated that the expressions of cleaved poly(ADP‑ribose) polymerase (PARP) and cleaved caspase 3 were markedly increased in the juglone combined with TRAIL group. Exposure to TRAIL alone did not induce the production of reactive oxygen species (ROS), activation of p38 orincrease of p53 in the TRAIL‑resistant melanoma cells, as determined by flow cytometry and western blot analysis. However, exposure to TRAIL in combination with juglone markedly increased the production of ROS, activated p38 and increased p53, compared with the cells treated with either juglone or TRAIL alone. Pretreatment with N‑acetyl cysteine, a ROS scavenger, significantly reduced the cytotoxicity of juglone in combination with TRAIL, which further supported that ROS was involved in the juglone‑induced sensitization of TRAIL. In conclusion, juglone potentiated TRAIL‑induced apoptosis in melanoma cells, and these effects were partially mediated through the ROS‑p38‑p53 pathway. These findings suggested that juglone may be a potential sensitizer for TRAIL therapy in the treatment of melanoma.

Icariside II (IS) is a metabolite of icariin, which is derived from Herba Epimedii. In the present study, the antiproliferative effects of IS on A375 human melanoma cells were examined in vitro and a possible mechanism through the ROS-p38-p53 pathway is discussed. A cell WST-8 assay revealed that treatment with IS markedly reduced cell viability from 77 to 21% (25 and 100 µM, respectively), and cell counting demonstrated that IS treatment reduced cell proliferation. IS treatment also induced cell cycle arrest of A375 cells at the G0/G1 and G2/M transitions and inhibited the expression of cell-cycle related proteins, including cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin B1 and phosphorylated cyclin-dependent kinase 1 (P-CDK1). In this study, it was determined that IS inhibits cell proliferation and induces cell cycle arrest through the generation of reactive oxygen species and activation of p38 and p53. These findings were further supported by the evidence that pretreatment with N-acetyl-L-cysteine, SB203580 or pifithrin-α significantly blocked IS-induced reduction of cell viability, increase of cell death and cell cycle arrest. In conclusion, IS inhibits cell proliferation and induces cell cycle arrest. Crucially, it was confirmed that these effects were mediated at least in part by activating the ROS-p38-p53 pathway.

Melanoma is a highly malignant and drug-resistant disease that imposes a substantial economic burden on the world. There are many studies linking trace elements to diverse types of cancers, including melanoma. This review elucidates the relationship between trace elements exposure and melanoma. It was identified that copper, manganese, selenium, zinc, iron, and many other trace elements were associated with melanoma in humans. In terms of epidemiology, different elements have different correlations with melanoma. These trace elements affect the occurrence and development of melanoma through various mechanisms, such as oxidative stress and the MAPK pathway. The literature on the role of trace elements in the pathogenesis and treatment of melanoma depicts promising prospects for this field. [ABSTRACT FROM AUTHOR]

Background: The clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms. Methods: The potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue. Results: HLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors. Conclusions: HLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells. [ABSTRACT FROM AUTHOR]

BRAF inhibitors are some of the most effective drugs against melanoma; however, their clinical application is largely limited by drug resistance. Juglone, isolated from walnut trees, has demonstrated anti-tumour activity. In the present study, it was investigated whether juglone could enhance the responses to a BRAF inhibitor in melanoma cells (A375R and SK-MEL-5R) with an acquired resistance. These cells were treated with juglone alone, BRAF inhibitor (PLX4032) alone, or juglone combined with PLX4032. It was demonstrated that the combination of juglone and PLX4032 had synergistic effects on BRAF inhibitor-resistant melanoma cells. Juglone potentiated PLX4032-induced cytotoxicity and mitochondrial apoptosis in both A375R and SK-MEL-5R cells, which was accompanied by a decline in mitochondrial membrane potential and a decrease in Bcl-2/Bax ratio. Moreover, juglone combined with PLX4032 markedly increased the intracellular level of reactive oxygen species (ROS) and activated p38 and p53, as compared with juglone alone or PLX4032 alone. Pre-treatment with N-acetyl-L-cysteine, a ROS scavenger, completely reversed the cytotoxicity induced by juglone combined with PLX4032. In conclusion, juglone potentiated BRAF inhibitor-induced apoptosis in resistant melanoma cells, and these effects occurred partially through ROS and the p38-p53 pathway, suggesting the potential of juglone as a sensitizer to BRAF inhibitors in the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Background: Juglone is a natural pigment, which has cytotoxic effect against various human tumor cells. However, its cytotoxicity to glioma cells, especially to tumor stem-like cells (TSCs) has not been demonstrated.Methods: TSCs of glioma were enriched from U87 and two primary cells (SHG62, and SHG66) using serum-free medium supplemented with growth factors, including bFGF, EGF and B27. After treatment of juglone with gradient concentrations (0, 10, 20, and 40 μM), the viability and apoptosis of TSCs were evaluated by WST-8 assay and flow cytometry. Reactive oxygen species (ROS) was labeled by the cell-permeable fluorescent probe and detected with flow cytometry. ROS scavenger (NAC) and p38-MAPK inhibitor (SB203580) were applied to resist the cytotoxic effect. Caspase 9 cleavage and p38 phosphorylation (P-p38) were quantified by western blot. Juglone as well as temozolomide (TMZ) were administrated in intracranial xenografts and MR scan was performed every week to evaluate the anti-tumor effect in vivo.Results: Juglone could obviously inhibit the proliferation of TSCs in glioma by decreasing cell viability (P < 0.01) and inducing apoptosis (P < 0.01), which was accompanied by increased caspase 9 cleavage in a dose-dependent manner (P < 0.01). In the meantime, juglone could generate ROS significantly and increase p38 phosphorylation (P < 0.01). In addition, pretreatment with ROS scavenger or p38-MAPK inhibitor could reverse juglone-induced cytotoxicity (P < 0.01). More importantly, juglone could also suppress tumor growth in vivo and improve the survival of U87-bearing mice compared with control (P < 0.05), although TMZ seemed to have better effect.Conclusions: Juglone could inhibit the growth of TSCs in gliomas through the activation of ROS-p38-MAPK pathway in vitro, and the anti-glioma effect was validated in vivo, which offers a potential therapeutic agent to gliomas. [ABSTRACT FROM AUTHOR]