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Published on: June 7, 2019
Imatinib mesylate induction of ROS-dependent apoptosis in melanoma B16F0 cells
Shao-Ping Chang1, Shing-Chuan Shen, Woan-Rouh Lee
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Background:
Imatinib mesylate (STI571), a protein tyrosine kinase inhibitor, was shown to reduce the viability of several cancer cell lines via apoptosis induction; however, the role of reactive oxygen species (ROS) in STI571-induced melanoma cell apoptosis is still undefined.
Objective:
In this study, we investigated the contribution of ROS to STI571-induced apoptosis in melanoma B16F0 cells, and the apoptotic mechanism elicited by STI571 was illustrated.
Methods:
Using an in vitro cell culture system, the effects of STI571 on ROS production, cell cycle progression, caspase activation, and mitochondrial functions were examined via Western blotting, a flow cytometric analysis, an enzyme activity assay, and a DNA integrity assay. In pharmacological studies, the ROS scavenger, N-acetyl cysteine (NAC), the NADPH oxidase inhibitor, dipheylene iodide (DPI), and mitogen-activated protein kinase (MAPK) inhibitors (PD98059, SP600125, and SB203580) were applied to investigate the mechanism.
Results:
STI571 reduced the viability of melanoma cells B16F0, but not human skin fibroblasts WS1, via apoptosis induction. Besides, apoptosis induced by STI571 was inhibited by the addition of NAC and DPI, and an increase in the intracellular peroxide level by STI571 was identified in melanoma B16F0 cells. Activation of caspases 3 and 9 enzyme activities accompanied by disrupting the mitochondria membrane potential in according with stimulating JNK and p38 protein phosphorylation was identified in STI571-treated B16F0 cells. STI571-mediated a ROS-dependent apoptosis potentiated by JNK inhibitor SP600125 was first identified in melanoma B16F0 cells.
Conclusion:
Our results support the idea that ROS-dependent apoptosis in STI571-treated melanoma cells B16F0. The combination of a JNK inhibitor with STI571 for treating melanomas is suggested for further in vivo studies.
Insights
Imatinib mesylate (STI571) induces apoptosis in melanoma cells by increasing reactive oxygen species (ROS). Combining STI571 with a JNK inhibitor may offer a new melanoma treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Imatinib mesylate (STI571), a tyrosine kinase inhibitor, induces apoptosis in cancer cells.
- The role of reactive oxygen species (ROS) in STI571-induced melanoma apoptosis remains unclear.
Purpose of the Study:
- Investigate the contribution of ROS to STI571-induced apoptosis in B16F0 melanoma cells.
- Elucidate the apoptotic mechanism of STI571 in melanoma.
Main Methods:
- In vitro cell culture, Western blotting, flow cytometry, enzyme activity assays, and DNA integrity assays were used.
- Pharmacological inhibitors (NAC, DPI, MAPK inhibitors) were employed to explore the mechanism.
Main Results:
- STI571 induced apoptosis in B16F0 melanoma cells but not WS1 fibroblasts.
- STI571 increased intracellular peroxide levels and ROS-dependent apoptosis, which was inhibited by NAC and DPI.
- STI571 activated caspases 3 and 9, disrupted mitochondrial membrane potential, and induced JNK/p38 phosphorylation.
Conclusions:
- STI571 induces ROS-dependent apoptosis in melanoma cells.
- Combining JNK inhibitors with STI571 is a potential therapeutic strategy for melanoma, warranting further in vivo investigation.
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