PMID- 29436614
OWN - NLM
STAT- MEDLINE
DCOM- 20180823
LR  - 20211204
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 52
IP  - 4
DP  - 2018 Apr
TI  - Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic 
      cell death and decreased ER expression in ER-positive human breast cancer cells.
PG  - 1339-1349
LID - 10.3892/ijo.2018.4271 [doi]
AB  - Arctigenin, a member of the Asteraceae family, is a biologically active lignan 
      that is consumed worldwide due to its several health benefits. However, its use 
      may pose a problem for patients with estrogen receptor (ER)alpha-positive breast 
      cancer, since studies have shown that arctigenin is a phytoestrogen that exerts a 
      proliferative effect by binding to the ER. Thus, in this study, we examined the 
      effect of arctigenin on ERalpha-positive MCF-7 human breast cancer cells to determine 
      whether the consumption of arctigenin is safe for patients with breast cancer. 
      First, we found that arctigenin inhibited the viability of the MCF-7 cells, and 
      colony formation assay confirmed that this effect was cytotoxic rather than 
      cytostatic. The cytotoxic effects were not mediated by cell cycle arrest, 
      apoptosis, or necroptosis, despite DNA damage, as indicated by poly(ADP-ribose) 
      polymerase (PARP) cleavage and phosphorylated H2A.X. An increase in lipidated 
      LC3, a marker of autophagosome formation, was observed, indicating that autophagy 
      was induced by arctigenin, which was found to be triggered by the inhibition of 
      the mechanistic target of rapamycin (mTOR) pathway. We then examined the effects 
      of arctigenin on ERalpha expression and determined whether it affects the sensitivity 
      of the cells to tamoxifen, as tamoxifen is commonly used against 
      hormone-responsive cancers and is known to act via the ERalpha. We found that 
      treatment with arctigenin effectively downregulated ERalpha expression, which was 
      found to be a consequence of the inhibition of the mTOR pathway. However, 
      treatment with arctigenin in combination with tamoxifen did not affect the 
      sensitivity of the cells to tamoxifen, but instead, exerted a synergistic effect. 
      On the whole, our data indicate that the phytoestrogen, arctigenin, mainly 
      targeted the mTOR pathway in ERalpha-positive MCF-7 human breast cancer cells, 
      leading to autophagy-induced cell death and the downregulation of ERalpha expression. 
      Furthermore, the synergistic effects between arctigenin and tamoxifen suggest 
      that the consumption of arctigenin is not only safe for patients with 
      hormone-sensitive cancers, but may also be an effective co-treatment.
FAU - Maxwell, Thressi
AU  - Maxwell T
AD  - Department of Pharmacology, School of Medicine and Intractable Disease Research 
      Center, Dongguk University, Gyeongju 38066, Republic of Korea.
FAU - Lee, Kyu Shik
AU  - Lee KS
AD  - Department of Pharmacology, School of Medicine and Intractable Disease Research 
      Center, Dongguk University, Gyeongju 38066, Republic of Korea.
FAU - Kim, Soyoung
AU  - Kim S
AD  - Department of Pharmacology, School of Medicine and Intractable Disease Research 
      Center, Dongguk University, Gyeongju 38066, Republic of Korea.
FAU - Nam, Kyung-Soo
AU  - Nam KS
AD  - Department of Pharmacology, School of Medicine and Intractable Disease Research 
      Center, Dongguk University, Gyeongju 38066, Republic of Korea.
LA  - eng
PT  - Journal Article
DEP - 20180209
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Furans)
RN  - 0 (Lignans)
RN  - 0 (Phytoestrogens)
RN  - 0 (Selective Estrogen Receptor Modulators)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - U76MR9VS6M (arctigenin)
SB  - IM
MH  - Autophagy/*drug effects
MH  - Drug Synergism
MH  - Estrogen Receptor alpha/biosynthesis/*drug effects
MH  - Female
MH  - Furans/*pharmacology
MH  - Humans
MH  - Lignans/*pharmacology
MH  - MCF-7 Cells
MH  - Phytoestrogens/*pharmacology
MH  - Selective Estrogen Receptor Modulators/pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*drug effects/metabolism
MH  - Tamoxifen/pharmacology
EDAT- 2018/02/14 06:00
MHDA- 2018/08/24 06:00
CRDT- 2018/02/14 06:00
PHST- 2017/11/07 00:00 [received]
PHST- 2018/02/06 00:00 [accepted]
PHST- 2018/02/14 06:00 [pubmed]
PHST- 2018/08/24 06:00 [medline]
PHST- 2018/02/14 06:00 [entrez]
AID - 10.3892/ijo.2018.4271 [doi]
PST - ppublish
SO  - Int J Oncol. 2018 Apr;52(4):1339-1349. doi: 10.3892/ijo.2018.4271. Epub 2018 Feb 
      9.