Selumetinib Inhibits Melanoma Metastasis to Mouse LiverviaSuppression of EMT-targeted Genes.
We investigated the therapeutic effects of a mitogen-activated protein (MEK) inhibitor, selumetinib, in a hepatic melanoma metastasis model and studied its possible mechanism of action.



Melanoma cell lines were exposed to selumetinib under different experimental conditions. We established a mouse model of liver metastasis and treated mice orally with vehicle or selumetinib and then evaluated metastasis progress.



Growth inhibition was observed in melanoma cells as a consequence of G1-phase cell-cycle arrest and the subsequent induction of apoptosis in a dose- and time-dependent manner. Mice with established liver metastases that were treated with selumetinib exhibited significantly less tumor progression than vehicle-treated mice. c-Myc expression in metastasized liver tissues were suppressed by selumetinib. Moreover, oral treatment with selumetinib modulated expression of epithelial-to-mesenchymal transition- and metastasis-related genes, including integrin alpha-5 (ITGA5), jagged 1 (JAG1), zinc finger E-box-binding homeobox 1 (ZEB1), NOTCH, and serpin peptidase inhibitor clade E (SERPINE1).



We established a mouse model of hepatic metastasis using a human melanoma cell line, such models are essential in elucidating the therapeutic effects of anti-metastatic drugs. Our data suggest the possibility that selumetinib presents a new strategy to treat liver metastasis in patients with melanoma by suppressing epithelial-to-mesenchymal transition-related genes.
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Seung-Hee
SH
Ryu
Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
Seung-Ho
SH
Heo
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Eun Young
EY
Park
Department of Biomedical Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Kyung-Chul
KC
Choi
Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
Je-Won
JW
Ryu
Department of Radiation Oncology, Gachon University Gil Medical Center, Incheon, Republic of Korea.
Seok Ho
SH
Lee
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea lsw@amc.seoul.kr.
Sang-Wook
SW
Lee
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C517975:AZD 6244; D001562:Benzimidazoles; D039482:Integrin alpha5; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D053773:Transforming Growth Factor beta1
EMT; MEK inhibitor; liver metastasis; melanoma; selumetinib (AZD6244)