PMID- 26496900
OWN - NLM
STAT- MEDLINE
DCOM- 20160922
LR  - 20211203
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Linking)
VI  - 12
IP  - 6
DP  - 2015 Dec
TI  - CXC195 induces apoptosis and endoplastic reticulum stress in human hepatocellular 
      carcinoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway.
PG  - 8229-36
LID - 10.3892/mmr.2015.4479 [doi]
AB  - CXC195 exhibits strong protective effects against neuronal apoptosis by exerting 
      antioxidant activity. However, the pharmacological function of CXC195 in cancer 
      remains to be elucidated. The present study demonstrated that CXC195 exhibited 
      significant cytotoxic effects, and induced cell cycle arrest and apoptosis in 
      HepG2 human hepatocellular carcinoma (HCC) cell lines. Following treatment of 
      HepG2 cells with 150 microMu CXC195 for 24 , cell viability and the apoptotic rate 
      were assessed using an MTT assay and Annexin V/propidium iodide staining followed 
      by  fl ow cytometric analysis. Molecular markers of the cell cycle, apoptosis, 
      mitochondrial function and endoplasmic reticulum (ER) stress were analyzed by 
      western blot or polymerase chain reaction analysis. Caspase activation, 
      cytochrome c and apoptosis‑inducing factor release, and analysis of the B cell 
      lymphoma 2 (Bcl‑2)‑associated X protein/Bcl‑2 ratio demonstrated that the 
      anticancer effects of CXC195 in HepG2 cells were mediated by caspase and 
      mitochondria‑dependent apoptosis. CXC195 also induced the expression of ER 
      stress‑associated proteins, including CCAAT‑enhancer‑binding protein homologous 
      protein, and glucose‑regulated proteins 94 and 78, and led to the activation of 
      multiple branches of ER stress transducers, including inositol‑requiring 
      enzyme 1alpha‑apoptosis signal‑regulating kinase‑p38/c‑Jun N‑terminal kinase, and 
      protein kinase R‑like endoplasmic reticulum kinase‑eukaryotic translation 
      initiation factor 2alpha‑activating transcription factor (ATF)4 and ATF6, in the 
      HepG2 cells. In addition, CXC195 inhibited the phosphorylation of 
      phosphoinositide 3‑kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) in 
      the HepG2 cells. These effects were enhanced following treatment with selected 
      inhibitors of PI3K (LY294002), Akt (SH‑6) and mTOR (rapamycin). Furthermore, 
      these inhibitors enhanced the pro‑apoptotic effects of CXC195 in the HepG2 cells. 
      In conclusion, the results of the present study indicated that CXC195 induced 
      apoptosis and ER stress in HepG2 cells through the inhibition of the 
      PI3K/Akt/mTOR signaling pathway.
FAU - Chen, Xiao-Liang
AU  - Chen XL
AD  - Department of Surgery, School of Medicine, Nanchang University, Nanchang, Jiangxi 
      330006, P.R. China.
FAU - Fu, Jian-Ping
AU  - Fu JP
AD  - Department of Hepatobiliary Surgery, Jiangxi Provincial People's Hospital, 
      Nanchang, Jiangxi 330006, P.R. China.
FAU - Shi, Jun
AU  - Shi J
AD  - Department of Hepatobiliary Surgery, The First Affiliated Hospital of Nanchang 
      University, Nanchang, Jiangxi 330006, P.R. China.
FAU - Wan, Ping
AU  - Wan P
AD  - Department of Hepatobiliary Surgery, Jiangxi Provincial People's Hospital, 
      Nanchang, Jiangxi 330006, P.R. China.
FAU - Cao, Hong
AU  - Cao H
AD  - Department of Hepatobiliary Surgery, Jiangxi Provincial People's Hospital, 
      Nanchang, Jiangxi 330006, P.R. China.
FAU - Tang, Zhi-Mou
AU  - Tang ZM
AD  - Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 
      330006, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20151023
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CXC 195)
RN  - 0 (Piperazines)
RN  - 0 (Pyrazines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Carcinoma, Hepatocellular/*metabolism/pathology
MH  - Cell Proliferation/drug effects
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Piperazines/chemistry/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Pyrazines/chemistry/*pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
EDAT- 2015/10/27 06:00
MHDA- 2016/09/23 06:00
CRDT- 2015/10/27 06:00
PHST- 2014/12/18 00:00 [received]
PHST- 2015/09/16 00:00 [accepted]
PHST- 2015/10/27 06:00 [entrez]
PHST- 2015/10/27 06:00 [pubmed]
PHST- 2016/09/23 06:00 [medline]
AID - 10.3892/mmr.2015.4479 [doi]
PST - ppublish
SO  - Mol Med Rep. 2015 Dec;12(6):8229-36. doi: 10.3892/mmr.2015.4479. Epub 2015 Oct 
      23.