RRC ID |
47984
|
著者 |
Satoh R, Hagihara K, Matsuura K, Manse Y, Kita A, Kunoh T, Masuko T, Moriyama M, Moriyama H, Tanabe G, Muraoka O, Sugiura R.
|
タイトル |
Identification of ACA-28, a 1'-acetoxychavicol acetate analogue compound, as a novel modulator of ERK MAPK signaling, which preferentially kills human melanoma cells.
|
ジャーナル |
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.
|
巻・号 |
22(7)
|
ページ |
608-618
|
公開日 |
2017-7-1
|
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 |
1.655
|
引用数 |
6
|
リソース情報 |
酵母 |
S. pombe strains |