title: Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.
abstract: The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.
authors: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Masami
authors: M
authors: Suzuki
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Fumiko
authors: F
authors: Chiwaki
authors: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Yumi
authors: Y
authors: Sawada
authors: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Maho
authors: M
authors: Ashikawa
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Kazuhiko
authors: K
authors: Aoyagi
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors: Takeshi
authors: T
authors: Fujita
authors: Division of Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital East, Chiba, Japan.
authors: Kazuyoshi
authors: K
authors: Yanagihara
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Masayuki
authors: M
authors: Komatsu
authors: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors: Minoru
authors: M
authors: Narita
authors: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors: Tsutomu
authors: T
authors: Suzuki
authors: International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Hiroshi
authors: H
authors: Nagase
authors: Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.
authors: Ryoji
authors: R
authors: Kushima
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors: Hiromi
authors: H
authors: Sakamoto
authors: Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors: Takeo
authors: T
authors: Fukagawa
authors: Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors: Hitoshi
authors: H
authors: Katai
authors: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.
authors: Hitoshi
authors: H
authors: Nakagama
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors: Teruhiko
authors: T
authors: Yoshida
authors: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Yasuhito
authors: Y
authors: Uezono
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Hiroki
authors: H
authors: Sasaki
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000008:administration & dosage; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D011957:Receptors, Opioid / Q000096:biosynthesis* / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D006131:Growth Inhibitors; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; D011957:Receptors, Opioid; D043823:Taxoids; C033593:methionine-enkephalin receptor; C032257:methylnaltrexone; D000077143:Docetaxel; D009271:Naltrexone