RRC ID 47984
Author Satoh R, Hagihara K, Matsuura K, Manse Y, Kita A, Kunoh T, Masuko T, Moriyama M, Moriyama H, Tanabe G, Muraoka O, Sugiura R.
Title Identification of ACA-28, a 1'-acetoxychavicol acetate analogue compound, as a novel modulator of ERK MAPK signaling, which preferentially kills human melanoma cells.
Journal Genes Cells
Abstract The extracellular signal-regulated kinase (ERK) signaling pathway is essential for cell proliferation and is frequently deregulated in human tumors such as melanoma. Melanoma remains incurable despite the use of conventional chemotherapy; consequently, development of new therapeutic agents for melanoma is highly desirable. Here, we carried out a chemical genetic screen using a fission yeast phenotypic assay and showed that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), which is a natural ginger compound, effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. ACA-28 more potently inhibited the growth of melanoma cells than did the parental compound ACA. Importantly, the growth of normal human epidermal melanocytes (NHEM) was less affected by ACA-28 at the same 50% inhibitory concentration. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells which were oncogenically transformed with human epidermal growth factor receptor-2 (HER2/ErbB2), but not in the parental cells. Notably, the ACA-28-induced apoptosis in melanoma and HER2-transformed cells was abrogated when ERK activation was blocked with a specific MEK inhibitor U0126. Consistently, ACA-28 more strongly stimulated ERK phosphorylation in melanoma cells, as compared in NHEM. ACA-28 might serve as a promising seed compound for melanoma treatment.
Volume 22(7)
Pages 608-618
Published 2017-7
DOI 10.1111/gtc.12499
PMID 28485554
MeSH 3T3 Cells Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Apoptosis / drug effects Benzyl Alcohols / chemistry Benzyl Alcohols / pharmacology* Butadienes / pharmacology Cell Line, Tumor Cell Transformation, Neoplastic / drug effects Cell Transformation, Neoplastic / pathology Enzyme Inhibitors / pharmacology Extracellular Signal-Regulated MAP Kinases / metabolism Gene Expression Regulation, Enzymologic / drug effects Humans MAP Kinase Kinase 1 / antagonists & inhibitors Melanocytes / cytology Melanocytes / drug effects Melanocytes / metabolism Melanoma / drug therapy* Melanoma / metabolism Melanoma / pathology Mice Nitriles / pharmacology Phosphorylation / drug effects Signal Transduction / drug effects
IF 1.922
Yeast S. pombe strains