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Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition.
Cell Physiol Biochem. 2018; 48(6):2231-2246.CP

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Liao KF
Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. Department of Internal Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan.
Chiu TL
School of Medicine, Tzu Chi University, Hualien, Taiwan. Division of Neuro-Oncology, Neuro-Medical Scientific Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
Huang SY
Department of Ophthalmology, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan.
Hsieh TF
School of Medicine, Tzu Chi University, Hualien, Taiwan. Department of Urology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan.
Chang SF
Department of Research, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan.
Ruan JW
Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.
Chen SP
Tzu Chi Stem Cells Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
Pang CY
Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan. Institute of Medical Sciences, School of Medicine, Tzu Chi University, Hualien, Taiwan.
Chiu SC
Department of Research, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan. Department of Laboratory Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan. General Education Center, Tzu Chi University of Science and Technology, Hualien, Taiwan.

MeSH

Angelica sinensisAnimalsAntineoplastic Agents, PhytogenicApoptosisCase-Control StudiesCell Line, TumorFemaleHumansMaleMiceMice, Inbred NODMice, SCIDPhthalic AnhydridesProportional Hazards ModelsSignal TransductionStomach NeoplasmsSurvival RateTOR Serine-Threonine KinasesTranscription FactorsTranscriptome

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30114701

Citation

Liao, Kuan-Fu, et al. "Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide On Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition." Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, vol. 48, no. 6, 2018, pp. 2231-2246.
Liao KF, Chiu TL, Huang SY, et al. Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition. Cell Physiol Biochem. 2018;48(6):2231-2246.
Liao, K. F., Chiu, T. L., Huang, S. Y., Hsieh, T. F., Chang, S. F., Ruan, J. W., Chen, S. P., Pang, C. Y., & Chiu, S. C. (2018). Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 48(6), 2231-2246. https://doi.org/10.1159/000492641
Liao KF, et al. Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide On Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition. Cell Physiol Biochem. 2018;48(6):2231-2246. PubMed PMID: 30114701.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: 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, Y1 - 2018/08/16/ PY - 2017/10/25/received PY - 2018/08/06/accepted PY - 2018/8/17/pubmed PY - 2018/9/11/medline PY - 2018/8/17/entrez KW - Gastric cancer KW - MTOR KW - Metastasis KW - N-butylidenephthalide KW - REDD1 SP - 2231 EP - 2246 JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology JO - Cell Physiol Biochem VL - 48 IS - 6 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. SN - 1421-9778 UR - https://www.unboundmedicine.com/medline/citation/30114701/Anti_Cancer_Effects_of_Radix_Angelica_Sinensis__Danggui__and_N_Butylidenephthalide_on_Gastric_Cancer:_Implications_for_REDD1_Activation_and_mTOR_Inhibition_ DB - PRIME DP - Unbound Medicine ER -