Cudraflavone C Induces Apoptosis of A375.S2 Melanoma Cells through Mitochondrial ROS Production and MAPK Activation.

Abstract

Melanoma is the most malignant form of skin cancer and is associated with a very poor prognosis. The aim of this study was to evaluate the apoptotic effects of cudraflavone C on A375.S2 melanoma cells and to determine the underlying mechanisms involved in apoptosis. Cell viability was determined using the MTT and real-time cytotoxicity assays. Flow cytometric evaluation of apoptosis was performed after staining the cells with Annexin V-FITC and propidium iodide. The mitochondrial membrane potential was evaluated using the JC-1 assay. Cellular ROS production was measured using the CellROX assay, while mitochondrial ROS production was evaluated using the MitoSOX assay. It was observed that cudraflavone C inhibited growth in A375.S2 melanoma cells, and promoted apoptosis via the mitochondrial pathway mediated by increased mitochondrial ROS production. In addition, cudraflavone C induced phosphorylation of MAPKs (p38, ERK, and JNK) and up-regulated the expression of apoptotic proteins (Puma, Bax, Bad, Bid, Apaf-1, cytochrome C, caspase-9, and caspase-3/7) in A375.S2 cells. Pretreatment of A375.S2 cells with MitoTEMPOL (a mitochondria-targeted antioxidant) attenuated the phosphorylation of MAPKs, expression of apoptotic proteins, and the overall progression of apoptosis. In summary, cudraflavone C induced apoptosis in A375.S2 melanoma cells by increasing mitochondrial ROS production; thus, activating p38, ERK, and JNK; and increasing the expression of apoptotic proteins. Therefore, cudraflavone C may be regarded as a potential form of treatment for malignant melanoma.

• Authors: Chiang-Wen Lee, Feng-Lin Yen, Horng-Huey Ko, Shu-Yu Li, Yao-Chang Chiang, Ming-Hsueh Lee, Ming-Horng Tsai, Lee-Fen Hsu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 18 Issue 7 (Jul 13 2017) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 28703746 (Publication Type: Journal Article)

Chemical References

• Flavones
• Neoplasm Proteins
• Reactive Oxygen Species
• cudraflavone C
• Mitogen-Activated Protein Kinases
• Caspases

Topics

• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Flavones (chemistry, pharmacology)
• Humans
• Melanoma (enzymology, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Neoplasm Proteins (metabolism)
• Phosphorylation (drug effects)
• Reactive Oxygen Species (metabolism)