PMID- 20159939
OWN - NLM
STAT- MEDLINE
DCOM- 20100528
LR  - 20210223
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Linking)
VI  - 77
IP  - 5
DP  - 2010 May
TI  - The synthetic cannabinoid WIN 55,212-2 sensitizes hepatocellular carcinoma cells 
      to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced 
      apoptosis by activating p8/CCAAT/enhancer binding protein homologous protein 
      (CHOP)/death receptor 5 (DR5) axis.
PG  - 854-63
LID - 10.1124/mol.109.062257 [doi]
AB  - In this article, we demonstrate that the synthetic cannabinoid 
      R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)-(1-naphthalenyl) 
      methanone mesylate (WIN 55,212-2) sensitizes human hepatocellular carcinoma (HCC) 
      cells to apoptosis mediated by tumor necrosis-related apoptosis inducing ligand 
      (TRAIL). The apoptotic mechanism induced by treatment with WIN/TRAIL combination 
      involved the loss of the mitochondrial transmembrane potential and led to the 
      activation of caspases. In HCC cells, WIN treatment induced the up-regulation of 
      TRAIL death receptor DR5, an effect that seemed to be related to the increase in 
      the level of p8 and CHOP, two factors implicated in cellular stress response and 
      apoptosis. This relationship was suggested by the observation that the 
      down-regulation of p8 or CHOP by specific small interfering RNAs attenuated both 
      WIN-mediated DR5 up-regulation and the cytotoxicity induced by WIN/TRAIL 
      cotreatment. Moreover, WIN induced a significant decrease in the levels of some 
      survival factors (survivin, c-inhibitor of apoptosis protein 2, and Bcl-2) and in 
      particular in that of the active phosphorylated form of AKT. This event seemed to 
      be dependent on the transcription factor peroxisome proliferator-activated 
      receptor-gamma whose level significantly increased after WIN treatment. 
      Therefore, both the induction of DR5 via p8 and CHOP and the down-regulation of 
      survival factors seem to be crucial for the marked synergistic effects induced by 
      the two drugs in HCC cells. Taken together, the results reported in this article 
      indicate that WIN/TRAIL combination could represent a novel important tool for 
      the treatment of HCC.
FAU - Pellerito, O
AU  - Pellerito O
AD  - Dipartimento di Scienze Biochimiche, Universita degli Studi di Palermo, Palermo, 
      Italy.
FAU - Calvaruso, G
AU  - Calvaruso G
FAU - Portanova, P
AU  - Portanova P
FAU - De Blasio, A
AU  - De Blasio A
FAU - Santulli, A
AU  - Santulli A
FAU - Vento, R
AU  - Vento R
FAU - Tesoriere, G
AU  - Tesoriere G
FAU - Giuliano, M
AU  - Giuliano M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100216
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Benzoxazines)
RN  - 0 (Cannabinoids)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (DNA Primers)
RN  - 0 (DNA, Complementary)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Morpholines)
RN  - 0 (Naphthalenes)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 5H31GI9502 
      ((3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone)
SB  - IM
MH  - Apoptosis/drug effects/*physiology
MH  - Benzoxazines/*pharmacology
MH  - Cannabinoids/*pharmacology
MH  - Carcinoma, Hepatocellular/*metabolism/pathology
MH  - Cell Line, Tumor/drug effects/physiology
MH  - DNA Primers
MH  - DNA, Complementary/drug effects/genetics
MH  - DNA, Neoplasm/drug effects/genetics
MH  - Flow Cytometry
MH  - Gene Amplification
MH  - Humans
MH  - Liver Neoplasms/*metabolism
MH  - Membrane Potentials/drug effects/physiology
MH  - Mitochondrial Membranes/drug effects/physiology
MH  - Morpholines/*pharmacology
MH  - Naphthalenes/*pharmacology
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/drug effects/*physiology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - TNF-Related Apoptosis-Inducing Ligand/*pharmacology
MH  - Transcription Factor CHOP/drug effects/*physiology
EDAT- 2010/02/18 06:00
MHDA- 2010/05/29 06:00
CRDT- 2010/02/18 06:00
PHST- 2010/02/18 06:00 [entrez]
PHST- 2010/02/18 06:00 [pubmed]
PHST- 2010/05/29 06:00 [medline]
AID - mol.109.062257 [pii]
AID - 10.1124/mol.109.062257 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2010 May;77(5):854-63. doi: 10.1124/mol.109.062257. Epub 2010 Feb 
      16.