Icariside II overcomes BRAF inhibitor resistance in melanoma by inducing ROS production and inhibiting MITF.

Abstract

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.

• Authors: Xiao Liu, Zheng Li, Ming Li, Jingxiu Chai, Shan He, Jinfeng Wu, Jinhua Xu
• Journal: Oncology reports (Oncol Rep) Vol. 44 Issue 1 Pg. 360-370 (07 2020) ISSN: 1791-2431 [Electronic] Greece
• PMID: 32319656 (Publication Type: Journal Article)

Chemical References

• Flavonoids
• MITF protein, human
• Microphthalmia-Associated Transcription Factor
• Reactive Oxygen Species
• baohuoside I
• Vemurafenib
• MET protein, human
• Proto-Oncogene Proteins c-met
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Cell Line, Tumor
• Cell Survival (drug effects)
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Flavonoids (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (drug therapy, genetics, metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Microphthalmia-Associated Transcription Factor (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins c-met (genetics)
• Reactive Oxygen Species (metabolism)
• Vemurafenib (pharmacology)