Nilotinib induction of melanogenesis via reactive oxygen species-dependent JNK activation in B16F0 mouse melanoma cells.

Abstract

Nilotinib (AMN), a second-generation tyrosine kinase inhibitor, induces apoptosis in various cancer cells, and our recent study showed that AMN effectively reduced the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis. The effect of AMN in the melanogenesis of melanoma cells is still unclear. In the present study, we found that the addition of AMN but not imatinib (STI) significantly increased the darkness of B16F0 melanoma cells, and the absorptive value increased with the concentration of AMN. A decrease in the viability of B16F0 cells by AMN was detected in a concentration-dependent manner, accompanied by increased DNA ladders, hypodiploid cells and cleavage of the caspase-3 protein. An in vitro tyrosinase (TYR) activity assay showed that increased TYR activity by AMN was detected in a concentration-dependent manner; however, induction of TYR activity by STI at a concentration of 40 μmol/L was observed. Increased intracellular peroxide by AMN was detected in B16F0 cells, and application of the antioxidant, N-acetylcysteine (NAC), significantly reduced AMN-induced peroxide production which also reduced the darkness of B16F0 cells. Additionally, AMN induced c-Jun N-terminal kinase (JNK) protein phosphorylation in B16F0 cells, which was inhibited by the addition of NAC. AMN-induced melanogenesis of B16F0 cells was significantly inhibited by the addition of NAC and the JNK inhibitor, SP600125 (SP). Data of Western blotting showed that increased protein levels of melanogenesis-related enzymes of tyrosinase-related protein-1 (TRP1), TRP2 and TYR were observed in AMN-treated B16F0 cells which were inhibited by the addition of NAC and SP. Evidence is provided supporting AMN effectively inducing the melanogenesis of B16F0 melanoma cells via reactive oxygen species-dependent JNK activation.

• Authors: Shao-Ping Chang, Huei-Mei Huang, Shing-Chuan Shen, Woan-Ruoh Lee, Yen-Chou Chen
• Journal: Experimental dermatology (Exp Dermatol) Vol. 27 Issue 12 Pg. 1388-1394 (12 2018) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 30290020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Anthracenes
• Antioxidants
• Melanins
• Pyrimidines
• Reactive Oxygen Species
• pyrazolanthrone
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• MAP Kinase Kinase 4
• Caspase 3
• nilotinib

Topics

• Animals
• Anthracenes (pharmacology)
• Antioxidants (metabolism)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Survival
• Enzyme Activation
• Imatinib Mesylate (pharmacology)
• MAP Kinase Kinase 4 (metabolism)
• Melanins (biosynthesis)
• Melanocytes (cytology)
• Melanoma, Experimental (metabolism)
• Mice
• Mitochondria (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Pyrimidines (pharmacology)
• Reactive Oxygen Species (metabolism)