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.
Keywords: juglone; BraF inhibitor resistance; melanoma; reactive oxygen species; p38.