Glutamate release inhibitor, Riluzole, inhibited proliferation of human hepatocellular carcinoma cells by elevated ROS production.
Liver cancer is one of the common malignancies in many countries and an increasing cause of cancer death. Despite of that, there are few therapeutic options available with inconsistent outcome, raising a need for developing alternative therapeutic options. Through a drug repositioning screening, we identified and investigated the action mechanism of the Riluzole, an amyotrophic lateral sclerosis (ALS) drug, on hepatocellular carcinoma (HCC) therapy. Treatment of the Riluzole leads to a suppression of cell proliferation in liver primary cancer cells and cancer cell lines. In addition, Riluzole induced caspase-dependent apoptosis and G2/M cell cycle arrest in SNU449 and Huh7 cell lines. In a line with the known function of glutamate release inhibitor, we found Riluzole-treated cells have increased the level of inner cellular glutamate that in turn decrease the glutathione (GSH) level and finally augment the reactive oxygen species (ROS) production. We confirm this finding in vivo by showing the Riluzole-induced GSH and ROS changes in a Huh7 xenograft cancer model. Altogether, these data suggest the anti-cancer effect of Riluzole on hepatocellular carcinoma and the suppression of glutamate signaling might be a new target pathway for HCC therapy.
Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Hyang Sook
HS
Seol
Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Sang Eun
SE
Lee
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Joon Seon
JS
Song
Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Hye Yong
HY
Lee
Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Sojung
S
Park
Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Inki
I
Kim
Basic Research Laboratory, Stem Cell Regulation and Animal Aging Section, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. Electronic address: singhshr@mail.nih.gov.
Shree Ram
SR
Singh
Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. Electronic address: suhwan.chang@amc.seoul.kr.
Suhwan
S
Chang
Asan Institute for Life Science, Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. Electronic address: jangsejin@amc.seoul.kr.
Se Jin
SJ
Jang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D018691:Excitatory Amino Acid Antagonists; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D019782:Riluzole; D005978:Glutathione
Drug repositioning; Hepatocellular carcinoma; ROS; Riluzole