PMID- 30710454
OWN - NLM
STAT- MEDLINE
DCOM- 20200424
LR  - 20210730
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 176
IP  - 7
DP  - 2019 Apr
TI  - Potent effects of dioscin against hepatocellular carcinoma through regulating 
      TP53-induced glycolysis and apoptosis regulator (TIGAR)-mediated apoptosis, 
      autophagy, and DNA damage.
PG  - 919-937
LID - 10.1111/bph.14594 [doi]
AB  - BACKGROUND AND PURPOSE: Dioscin shows potent effects against cancers. We aimed to 
      elucidate its pharmacological effects and mechanisms of action on hepatocellular 
      carcinoma (HCC) in vivo and in vitro. EXPERIMENTAL APPROACH: Effects of dioscin 
      were investigated in SMMC7721 and HepG2 cells, diethylnitrosamine-induced primary 
      liver cancer in rats, and cell xenografts in nude mice. Isobaric tags for 
      relative and absolution quantitation (iTRAQ)-based proteomics was used to find 
      dioscin's targets and investigate its mechanism. KEY RESULTS: In SMMC7721 and 
      HepG2 cells dioscin markedly inhibited cell proliferation and migration, induced 
      apoptosis, autophagy, and DNA damage. It inhibited DEN-induced primary liver 
      cancer in rats, markedly changed body weights and restored levels of alpha 
      fetoprotein, alanine transaminase, aspartate transaminase, gamma-glutamyltransferase, 
      alkaline phosphatase, and Ki67. It also inhibited growth of xenografts in mice. 
      In SMMC7721 cells, 191 differentially expressed proteins were found after 
      dioscin, based on iTRAQ-based assay. TP53-inducible glycolysis and apoptosis 
      regulator (TIGAR) was identified as being significantly down-regulated by 
      dioscin. Dioscin induced cell apoptosis, autophagy, and DNA damage via increasing 
      expression levels of p53, cleaved PARP, Bax, cleaved caspase-3/9, Beclin-1, and 
      LC3 and suppressing those of Bcl-2, p-Akt, p-mammalian target of rapamycin 
      (mTOR), CDK5, p-ataxia telangiectasia-mutated gene (ATM). The transfection of 
      TIGAR siRNA into SMMC7721 cells and xenografts in nude mice further confirmed 
      that the potent activity of dioscin against HCC is evoked by adjusting 
      TIGAR-mediated inhibition of p53, Akt/mTOR, and CDK5/ATM pathways. CONCLUSIONS 
      AND IMPLICATIONS: The data suggest that dioscin has potential as a therapeutic, 
      and TIGAR as a drug target for treating HCC.
CI  - (c) 2019 The British Pharmacological Society.
FAU - Mao, Zhang
AU  - Mao Z
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Han, Xu
AU  - Han X
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Chen, Dahong
AU  - Chen D
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Xu, Youwei
AU  - Xu Y
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Xu, Lina
AU  - Xu L
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Yin, Lianhong
AU  - Yin L
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Sun, Huijun
AU  - Sun H
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Qi, Yan
AU  - Qi Y
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Fang, Lingling
AU  - Fang L
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Liu, Kexin
AU  - Liu K
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
FAU - Peng, Jinyong
AU  - Peng J
AUID- ORCID: 0000-0002-6265-2667
AD  - College of Pharmacy, Dalian Medical University, Dalian, China.
AD  - Key Laboratory for Basic and Applied Research on Pharmacodynamic Substances of 
      Traditional Chinese Medicine of Liaoning Province, Dalian Medical University, 
      Dalian, China.
AD  - National-Local Joint Engineering Research Center for Drug Development (R&D) of 
      Neurodegenerative Diseases, Dalian Medical University, Dalian, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190318
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 3B95U4OLWV (dioscin)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - K49P2K8WLX (Diosgenin)
SB  - IM
EIN - Br J Pharmacol. 2019 Dec;176(24):4788. PMID: 31950491
EIN - Br J Pharmacol. 2021 Aug;178(16):3354-3355. PMID: 34327709
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Apoptosis Regulatory Proteins/genetics
MH  - Autophagy/drug effects
MH  - Carcinoma, Hepatocellular/*drug therapy/genetics/metabolism/pathology
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - DNA Damage
MH  - Diosgenin/*analogs & derivatives/pharmacology/therapeutic use
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Phosphoric Monoester Hydrolases/genetics
MH  - RNA, Small Interfering/genetics
MH  - Rats, Wistar
MH  - Tumor Suppressor Protein p53/metabolism
PMC - PMC6433650
COIS- The authors declare no conflicts of interest.
EDAT- 2019/02/03 06:00
MHDA- 2020/04/25 06:00
PMCR- 2020/04/01
CRDT- 2019/02/03 06:00
PHST- 2018/07/26 00:00 [received]
PHST- 2018/12/05 00:00 [revised]
PHST- 2018/12/18 00:00 [accepted]
PHST- 2019/02/03 06:00 [pubmed]
PHST- 2020/04/25 06:00 [medline]
PHST- 2019/02/03 06:00 [entrez]
PHST- 2020/04/01 00:00 [pmc-release]
AID - BPH14594 [pii]
AID - 10.1111/bph.14594 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2019 Apr;176(7):919-937. doi: 10.1111/bph.14594. Epub 2019 Mar 
      18.