Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer

Tomoharu Miyashita, Toru Kono, Daisuke Matsui, Yuki Yamazaki, Daichi Sadatomi, Naoki Fujitsuka, Shinichi Nakanuma, Koichi Okamoto, Isamu Makino, Jun Kinoshita, Keishi Nakamura, Katsunobu Oyama, Hidehiro Tajima, Hiroyuki Takamura, Itasu Ninomiya, Sachio Fushida, Kenichi Mukaisho, John Harmon, Tetsuo Ohta

Research output: Contribution to journalArticle

Abstract

Background: Prostaglandin E2 is one of the potential products that promotes development of tumors and also is a strong inducer of M2 phenotype macrophages, which contribute to tumor development in the immunosuppressed microenvironment. Hangeshashinto (TJ-14), a Japanese traditional medicine (Kampo medicine), has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2. We previously developed a surgical rat reflux model of esophageal cancer and used this well-established animal model to investigate the action of TJ-14 in preventing esophageal cancer. We also assessed the effect of TJ-14 on the downregulation of prostaglandin E2 production, utilizing esophageal squamous cell carcinoma cell line exposed to bile acid. Methods: An end-to-side esophagojejunostomy was performed for the reflux model. A daily oral diet was subsequently administered, consisting of either diet-incorporated TJ-14 or standard diet as a control group. The rats were killed at 40 weeks after surgery. The incidence of esophageal cancer, Barrett's metaplasia, and proliferative hyperplasia were assessed histologically. CD163, a M2 phenotype macrophage marker, was assessed with immunohistochemistry. Prostaglandin E2 enzyme immunoassay and lactate dehydrogenase assay were performed on chenodeoxycholic acid or gastroesophageal reflux contents exposed to esophageal squamous cell carcinoma cell line. Results: Sixty-seven percent of the controls (n = 12) developed esophageal cancer, but animals that received TJ-14 (n = 10) had a cancer incidence of 10% (P =.007). Barrett's metaplasia was found in 83% of the rats in the control group and 50% of the rats in the TJ-14 indicating a protective tendency of TJ-14 (P =.095). All of the rats developed proliferative hyperplasia. The number of M2 phenotype macrophage were significantly decreased in the TJ-14 group compared to the control group in both Barrett's metaplasia and esophageal cancer lesions. TJ-14 inhibited chenodeoxycholic acid or gastroesophageal reflux content–induced prostaglandin E2 production in esophageal squamous cell carcinoma cell. Conclusion: TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.

Original languageEnglish (US)
JournalSurgery (United States)
DOIs
StateAccepted/In press - Jan 1 2018

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Esophageal Neoplasms
Dinoprostone
Barrett Esophagus
Macrophages
Chenodeoxycholic Acid
Gastroesophageal Reflux
Diet
Phenotype
Control Groups
Hyperplasia
Incidence
hange-shashinto
Kampo Medicine
Anatomic Models
Cell Line
Neoplasms
Stomatitis
Traditional Medicine
Bile Acids and Salts
Immunoenzyme Techniques

ASJC Scopus subject areas

  • Surgery

Cite this

Miyashita, T., Kono, T., Matsui, D., Yamazaki, Y., Sadatomi, D., Fujitsuka, N., ... Ohta, T. (Accepted/In press). Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer. Surgery (United States). https://doi.org/10.1016/j.surg.2018.02.003

Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer. / Miyashita, Tomoharu; Kono, Toru; Matsui, Daisuke; Yamazaki, Yuki; Sadatomi, Daichi; Fujitsuka, Naoki; Nakanuma, Shinichi; Okamoto, Koichi; Makino, Isamu; Kinoshita, Jun; Nakamura, Keishi; Oyama, Katsunobu; Tajima, Hidehiro; Takamura, Hiroyuki; Ninomiya, Itasu; Fushida, Sachio; Mukaisho, Kenichi; Harmon, John; Ohta, Tetsuo.

In: Surgery (United States), 01.01.2018.

Research output: Contribution to journalArticle

Miyashita, T, Kono, T, Matsui, D, Yamazaki, Y, Sadatomi, D, Fujitsuka, N, Nakanuma, S, Okamoto, K, Makino, I, Kinoshita, J, Nakamura, K, Oyama, K, Tajima, H, Takamura, H, Ninomiya, I, Fushida, S, Mukaisho, K, Harmon, J & Ohta, T 2018, 'Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer', Surgery (United States). https://doi.org/10.1016/j.surg.2018.02.003
Miyashita, Tomoharu ; Kono, Toru ; Matsui, Daisuke ; Yamazaki, Yuki ; Sadatomi, Daichi ; Fujitsuka, Naoki ; Nakanuma, Shinichi ; Okamoto, Koichi ; Makino, Isamu ; Kinoshita, Jun ; Nakamura, Keishi ; Oyama, Katsunobu ; Tajima, Hidehiro ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Fushida, Sachio ; Mukaisho, Kenichi ; Harmon, John ; Ohta, Tetsuo. / Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer. In: Surgery (United States). 2018.
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abstract = "Background: Prostaglandin E2 is one of the potential products that promotes development of tumors and also is a strong inducer of M2 phenotype macrophages, which contribute to tumor development in the immunosuppressed microenvironment. Hangeshashinto (TJ-14), a Japanese traditional medicine (Kampo medicine), has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2. We previously developed a surgical rat reflux model of esophageal cancer and used this well-established animal model to investigate the action of TJ-14 in preventing esophageal cancer. We also assessed the effect of TJ-14 on the downregulation of prostaglandin E2 production, utilizing esophageal squamous cell carcinoma cell line exposed to bile acid. Methods: An end-to-side esophagojejunostomy was performed for the reflux model. A daily oral diet was subsequently administered, consisting of either diet-incorporated TJ-14 or standard diet as a control group. The rats were killed at 40 weeks after surgery. The incidence of esophageal cancer, Barrett's metaplasia, and proliferative hyperplasia were assessed histologically. CD163, a M2 phenotype macrophage marker, was assessed with immunohistochemistry. Prostaglandin E2 enzyme immunoassay and lactate dehydrogenase assay were performed on chenodeoxycholic acid or gastroesophageal reflux contents exposed to esophageal squamous cell carcinoma cell line. Results: Sixty-seven percent of the controls (n = 12) developed esophageal cancer, but animals that received TJ-14 (n = 10) had a cancer incidence of 10{\%} (P =.007). Barrett's metaplasia was found in 83{\%} of the rats in the control group and 50{\%} of the rats in the TJ-14 indicating a protective tendency of TJ-14 (P =.095). All of the rats developed proliferative hyperplasia. The number of M2 phenotype macrophage were significantly decreased in the TJ-14 group compared to the control group in both Barrett's metaplasia and esophageal cancer lesions. TJ-14 inhibited chenodeoxycholic acid or gastroesophageal reflux content–induced prostaglandin E2 production in esophageal squamous cell carcinoma cell. Conclusion: TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.",
author = "Tomoharu Miyashita and Toru Kono and Daisuke Matsui and Yuki Yamazaki and Daichi Sadatomi and Naoki Fujitsuka and Shinichi Nakanuma and Koichi Okamoto and Isamu Makino and Jun Kinoshita and Keishi Nakamura and Katsunobu Oyama and Hidehiro Tajima and Hiroyuki Takamura and Itasu Ninomiya and Sachio Fushida and Kenichi Mukaisho and John Harmon and Tetsuo Ohta",
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T1 - Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer

AU - Miyashita, Tomoharu

AU - Kono, Toru

AU - Matsui, Daisuke

AU - Yamazaki, Yuki

AU - Sadatomi, Daichi

AU - Fujitsuka, Naoki

AU - Nakanuma, Shinichi

AU - Okamoto, Koichi

AU - Makino, Isamu

AU - Kinoshita, Jun

AU - Nakamura, Keishi

AU - Oyama, Katsunobu

AU - Tajima, Hidehiro

AU - Takamura, Hiroyuki

AU - Ninomiya, Itasu

AU - Fushida, Sachio

AU - Mukaisho, Kenichi

AU - Harmon, John

AU - Ohta, Tetsuo

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Prostaglandin E2 is one of the potential products that promotes development of tumors and also is a strong inducer of M2 phenotype macrophages, which contribute to tumor development in the immunosuppressed microenvironment. Hangeshashinto (TJ-14), a Japanese traditional medicine (Kampo medicine), has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2. We previously developed a surgical rat reflux model of esophageal cancer and used this well-established animal model to investigate the action of TJ-14 in preventing esophageal cancer. We also assessed the effect of TJ-14 on the downregulation of prostaglandin E2 production, utilizing esophageal squamous cell carcinoma cell line exposed to bile acid. Methods: An end-to-side esophagojejunostomy was performed for the reflux model. A daily oral diet was subsequently administered, consisting of either diet-incorporated TJ-14 or standard diet as a control group. The rats were killed at 40 weeks after surgery. The incidence of esophageal cancer, Barrett's metaplasia, and proliferative hyperplasia were assessed histologically. CD163, a M2 phenotype macrophage marker, was assessed with immunohistochemistry. Prostaglandin E2 enzyme immunoassay and lactate dehydrogenase assay were performed on chenodeoxycholic acid or gastroesophageal reflux contents exposed to esophageal squamous cell carcinoma cell line. Results: Sixty-seven percent of the controls (n = 12) developed esophageal cancer, but animals that received TJ-14 (n = 10) had a cancer incidence of 10% (P =.007). Barrett's metaplasia was found in 83% of the rats in the control group and 50% of the rats in the TJ-14 indicating a protective tendency of TJ-14 (P =.095). All of the rats developed proliferative hyperplasia. The number of M2 phenotype macrophage were significantly decreased in the TJ-14 group compared to the control group in both Barrett's metaplasia and esophageal cancer lesions. TJ-14 inhibited chenodeoxycholic acid or gastroesophageal reflux content–induced prostaglandin E2 production in esophageal squamous cell carcinoma cell. Conclusion: TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.

AB - Background: Prostaglandin E2 is one of the potential products that promotes development of tumors and also is a strong inducer of M2 phenotype macrophages, which contribute to tumor development in the immunosuppressed microenvironment. Hangeshashinto (TJ-14), a Japanese traditional medicine (Kampo medicine), has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2. We previously developed a surgical rat reflux model of esophageal cancer and used this well-established animal model to investigate the action of TJ-14 in preventing esophageal cancer. We also assessed the effect of TJ-14 on the downregulation of prostaglandin E2 production, utilizing esophageal squamous cell carcinoma cell line exposed to bile acid. Methods: An end-to-side esophagojejunostomy was performed for the reflux model. A daily oral diet was subsequently administered, consisting of either diet-incorporated TJ-14 or standard diet as a control group. The rats were killed at 40 weeks after surgery. The incidence of esophageal cancer, Barrett's metaplasia, and proliferative hyperplasia were assessed histologically. CD163, a M2 phenotype macrophage marker, was assessed with immunohistochemistry. Prostaglandin E2 enzyme immunoassay and lactate dehydrogenase assay were performed on chenodeoxycholic acid or gastroesophageal reflux contents exposed to esophageal squamous cell carcinoma cell line. Results: Sixty-seven percent of the controls (n = 12) developed esophageal cancer, but animals that received TJ-14 (n = 10) had a cancer incidence of 10% (P =.007). Barrett's metaplasia was found in 83% of the rats in the control group and 50% of the rats in the TJ-14 indicating a protective tendency of TJ-14 (P =.095). All of the rats developed proliferative hyperplasia. The number of M2 phenotype macrophage were significantly decreased in the TJ-14 group compared to the control group in both Barrett's metaplasia and esophageal cancer lesions. TJ-14 inhibited chenodeoxycholic acid or gastroesophageal reflux content–induced prostaglandin E2 production in esophageal squamous cell carcinoma cell. Conclusion: TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.

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JF - Surgery

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