Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer

Implications for REDD1 Activation and mTOR Inhibition

Kuan Fu Liao, Tsung Lang Chiu, Sung Ying Huang, Teng Fu Hsieh, Shu Fang Chang, Jhen-Wei Ruan, Shee Ping Chen, Cheng Yoong Pang, Sheng Chun Chiu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002). The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

Original languageEnglish
Pages (from-to)2231-2236
Number of pages6
JournalCellular Physiology and Biochemistry
Volume48
Issue number6
DOIs
Publication statusPublished - 2018 Aug 1

Fingerprint

Angelica sinensis
Stomach Neoplasms
Neoplasms
Heterografts
RNA Sequence Analysis
Growth
Taiwan
butylidenephthalide
Survival Rate
Chinese Traditional Medicine
National Health Programs
Therapeutics
RNA Interference
Transcriptome
Antineoplastic Agents
Small Interfering RNA
Cell Movement
Transfection

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

Liao, Kuan Fu ; Chiu, Tsung Lang ; Huang, Sung Ying ; Hsieh, Teng Fu ; Chang, Shu Fang ; Ruan, Jhen-Wei ; Chen, Shee Ping ; Pang, Cheng Yoong ; Chiu, Sheng Chun. / Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer : Implications for REDD1 Activation and mTOR Inhibition. In: Cellular Physiology and Biochemistry. 2018 ; Vol. 48, No. 6. pp. 2231-2236.
@article{587b267dfcb148eeae70b1861b5316a4,
title = "Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition",
abstract = "Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002). The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 {\%} CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.",
author = "Liao, {Kuan Fu} and Chiu, {Tsung Lang} and Huang, {Sung Ying} and Hsieh, {Teng Fu} and Chang, {Shu Fang} and Jhen-Wei Ruan and Chen, {Shee Ping} and Pang, {Cheng Yoong} and Chiu, {Sheng Chun}",
year = "2018",
month = "8",
day = "1",
doi = "10.1159/000492641",
language = "English",
volume = "48",
pages = "2231--2236",
journal = "Cellular Physiology and Biochemistry",
issn = "1015-8987",
publisher = "S. Karger AG",
number = "6",

}

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer : Implications for REDD1 Activation and mTOR Inhibition. / Liao, Kuan Fu; Chiu, Tsung Lang; Huang, Sung Ying; Hsieh, Teng Fu; Chang, Shu Fang; Ruan, Jhen-Wei; Chen, Shee Ping; Pang, Cheng Yoong; Chiu, Sheng Chun.

In: Cellular Physiology and Biochemistry, Vol. 48, No. 6, 01.08.2018, p. 2231-2236.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer

T2 - Implications for REDD1 Activation and mTOR Inhibition

AU - Liao, Kuan Fu

AU - Chiu, Tsung Lang

AU - Huang, Sung Ying

AU - Hsieh, Teng Fu

AU - Chang, Shu Fang

AU - Ruan, Jhen-Wei

AU - Chen, Shee Ping

AU - Pang, Cheng Yoong

AU - Chiu, Sheng Chun

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002). The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

AB - Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002). The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

UR - http://www.scopus.com/inward/record.url?scp=85052631598&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052631598&partnerID=8YFLogxK

U2 - 10.1159/000492641

DO - 10.1159/000492641

M3 - Article

VL - 48

SP - 2231

EP - 2236

JO - Cellular Physiology and Biochemistry

JF - Cellular Physiology and Biochemistry

SN - 1015-8987

IS - 6

ER -