PMID- 25005758
OWN - NLM
STAT- MEDLINE
DCOM- 20150615
LR  - 20211203
IS  - 1432-1912 (Electronic)
IS  - 0028-1298 (Linking)
VI  - 387
IP  - 10
DP  - 2014 Oct
TI  - A unique amidoanthraquinone derivative displays antiproliferative activity 
      against human hormone-refractory metastatic prostate cancers through activation 
      of LKB1-AMPK-mTOR signaling pathway.
PG  - 979-90
LID - 10.1007/s00210-014-0998-9 [doi]
AB  - Hormone-refractory metastatic prostate cancer (HRMPC), which is metastatic and 
      resistant to hormone therapy, is an intractable problem in clinical treatment. 
      Anthraquinone-based natural products and synthetic compounds have shown 
      anticancer activity. However, cardiac toxicity is a major adverse reaction in 
      these compounds. CC-36, a unique anthraquinone derivative, displayed higher 
      antiproliferative activity in HRMPC than that in H9c2 cardiomyoblasts and normal 
      prostate cells with the selectivity of five and twelve times, respectively. CC-36 
      caused G1 arrest of the cell cycle associated with an upregulation of p21 and 
      downregulated levels of cyclin D1 and cyclin E expressions. Immunoprecipitation 
      assay and Western blotting analysis showed that CC-36 triggered an increase of 
      TSC1/TSC2 association and suppressed the phosphorylation of mammalian target of 
      rapamycin (mTOR) (Ser2448) and p70 ribosomal protein S6 kinase (p70S6K) (Thr389), 
      indicating the inhibition of both kinases' activities. CC-36 induced liver kinase 
      B1 (LKB1) phosphorylation at Thr189, leading to LKB1 translocation from nucleus 
      to cytosol for AMPKalpha phosphorylation (Thr172) and the kinase activation. The 
      signaling pathway was validated using small interfering RNA (siRNA) technique 
      with LKB1 knockdown. The combination treatment of MK2206 (a specific Akt 
      inhibitor) with CC-36 showed a synergistic apoptosis in PC-3 cells indicating a 
      potential combination strategy for LKB1 activators. Taken together, the data 
      suggest that CC-36 displays anti-HRMPC activity through the activation of 
      LKB1-AMPK pathway, leading to an inhibition of mTOR signaling and the induction 
      of G1 arrest of the cell cycle. The combination use of Akt inhibitors with agents 
      acting through LKB1-AMPK-mTOR pathway is a potential strategy for HRMPC 
      treatment.
FAU - Hsu, Jui-Ling
AU  - Hsu JL
AD  - School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, 
      Taipei, 100, Taiwan.
FAU - Liu, Shih-Ping
AU  - Liu SP
FAU - Lee, Chia-Chung
AU  - Lee CC
FAU - Hsu, Lih-Ching
AU  - Hsu LC
FAU - Ho, Yunn-Fang
AU  - Ho YF
FAU - Huang, Hsu-Shan
AU  - Huang HS
FAU - Guh, Jih-Hwa
AU  - Guh JH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140709
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
RN  - 0 (Anthraquinones)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Anthraquinones/chemistry/*pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects/*physiology
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Male
MH  - Myocytes, Cardiac/drug effects/metabolism
MH  - Prostatic Neoplasms, Castration-Resistant/drug therapy/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Signal Transduction/drug effects/*physiology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
EDAT- 2014/07/10 06:00
MHDA- 2015/06/16 06:00
CRDT- 2014/07/10 06:00
PHST- 2014/02/17 00:00 [received]
PHST- 2014/05/22 00:00 [accepted]
PHST- 2014/07/10 06:00 [entrez]
PHST- 2014/07/10 06:00 [pubmed]
PHST- 2015/06/16 06:00 [medline]
AID - 10.1007/s00210-014-0998-9 [doi]
PST - ppublish
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2014 Oct;387(10):979-90. doi: 
      10.1007/s00210-014-0998-9. Epub 2014 Jul 9.