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

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

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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 Docresistant 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 antitumor drugs.

Original language	English
Article number	e0123407
Journal	PLoS ONE
Volume	10
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0123407
State	Published - 8 Apr 2015
Externally published	Yes

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Suzuki, M., Chiwaki, F., Sawada, Y., Ashikawa, M., Aoyagi, K., Fujita, T., Yanagihara, K., Komatsu, M., Narita, M., Suzuki, T., Nagase, H., Kushima, R., Sakamoto, H., Fukagawa, T., Katai, H., Nakagama, H., Yoshida, T., Uezono, Y., & Sasaki, H. (2015). Peripheral opioid antagonist enhances the effect of anti-Tumor drug by blocking a cell growth-suppressive pathway in vivo. PLoS ONE, 10(4), Article e0123407. https://doi.org/10.1371/journal.pone.0123407

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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 Docresistant 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 antitumor drugs.",

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

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Suzuki, M, Chiwaki, F, Sawada, Y, Ashikawa, M, Aoyagi, K, Fujita, T, Yanagihara, K, Komatsu, M, Narita, M, Suzuki, T, Nagase, H, Kushima, R, Sakamoto, H, Fukagawa, T, Katai, H, Nakagama, H, Yoshida, T, Uezono, Y & Sasaki, H 2015, 'Peripheral opioid antagonist enhances the effect of anti-Tumor drug by blocking a cell growth-suppressive pathway in vivo', PLoS ONE, vol. 10, no. 4, e0123407. https://doi.org/10.1371/journal.pone.0123407

TY - JOUR

T1 - Peripheral opioid antagonist enhances the effect of anti-Tumor drug by blocking a cell growth-suppressive pathway in vivo

AU - Suzuki, Masami

AU - Chiwaki, Fumiko

AU - Sawada, Yumi

AU - Ashikawa, Maho

AU - Aoyagi, Kazuhiko

AU - Fujita, Takeshi

AU - Yanagihara, Kazuyoshi

AU - Komatsu, Masayuki

AU - Narita, Minoru

AU - Suzuki, Tsutomu

AU - Nagase, Hiroshi

AU - Kushima, Ryoji

AU - Sakamoto, Hiromi

AU - Fukagawa, Takeo

AU - Katai, Hitoshi

AU - Nakagama, Hitoshi

AU - Yoshida, Teruhiko

AU - Uezono, Yasuhito

AU - Sasaki, Hiroki

PY - 2015/4/8

Y1 - 2015/4/8

N2 - 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 Docresistant 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 antitumor drugs.

AB - 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 Docresistant 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 antitumor drugs.

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SN - 1932-6203

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JO - PLoS ONE

JF - PLoS ONE

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M1 - e0123407

ER -

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

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