Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo

Masami Suzuki; Fumiko Chiwaki; Yumi Sawada; Maho Ashikawa; Kazuhiko Aoyagi; Takeshi Fujita; Kazuyoshi Yanagihara; Masayuki Komatsu; Minoru Narita; Tsutomu Suzuki; Hiroshi Nagase; Ryoji Kushima; Hiromi Sakamoto; Takeo Fukagawa; Hitoshi Katai; Hitoshi Nakagama; Teruhiko Yoshida; Yasuhito Uezono; Hiroki Sasaki

doi:10.1371/journal.pone.0123407

Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo

PLoS One. 2015 Apr 8;10(4):e0123407. doi: 10.1371/journal.pone.0123407. eCollection 2015.

Authors

Masami Suzuki¹, Fumiko Chiwaki², Yumi Sawada¹, Maho Ashikawa¹, Kazuhiko Aoyagi², Takeshi Fujita³, Kazuyoshi Yanagihara⁴, Masayuki Komatsu², Minoru Narita⁵, Tsutomu Suzuki⁶, Hiroshi Nagase⁷, Ryoji Kushima⁸, Hiromi Sakamoto³, Takeo Fukagawa⁹, Hitoshi Katai⁹, Hitoshi Nakagama¹⁰, Teruhiko Yoshida³, Yasuhito Uezono¹, Hiroki Sasaki²

Affiliations

¹ Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
² Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
³ Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
⁴ Division of Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital East, Chiba, Japan.
⁵ Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
⁶ Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
⁷ International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
⁸ Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.
⁹ Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
¹⁰ Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols
Cell Cycle / drug effects
Cell Cycle / genetics
Cell Proliferation / drug effects
Docetaxel
Drug Synergism
Growth Inhibitors / biosynthesis
Growth Inhibitors / genetics
Humans
Mice
Naltrexone / administration & dosage
Naltrexone / analogs & derivatives*
Narcotic Antagonists / administration & dosage
Quaternary Ammonium Compounds / administration & dosage
Receptors, Opioid / biosynthesis*
Receptors, Opioid / genetics
Stomach Neoplasms / drug therapy*
Stomach Neoplasms / genetics
Stomach Neoplasms / pathology
Taxoids / administration & dosage*

Substances

Growth Inhibitors
Narcotic Antagonists
Quaternary Ammonium Compounds
Receptors, Opioid
Taxoids
methionine-enkephalin receptor
methylnaltrexone
Docetaxel
Naltrexone

Grants and funding

This work was supported by the National Institute of Biomedical Innovation (for the Advanced Research for Medical Products Mining Programme ID10-41, ID12-01), National Cancer Center Research and Development Fund (23-A-7, 23-B-6, 23-B-18, 25-A-6), The Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 25860432 and No. 23501322), and The Princess Takamatsu Cancer Research Fund. Drs. Suzuki and Fujita are the recipients of Research Resident Fellowships from the Foundation of Promotion of Cancer Research in Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.