PMID- 19461054
OWN - NLM
STAT- MEDLINE
DCOM- 20090817
LR  - 20211203
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Linking)
VI  - 76
IP  - 2
DP  - 2009 Aug
TI  - Antitumor effects of dehydroxymethylepoxyquinomicin, a novel nuclear 
      factor-kappaB inhibitor, in human liver cancer cells are mediated through a 
      reactive oxygen species-dependent mechanism.
PG  - 290-300
LID - 10.1124/mol.109.055418 [doi]
AB  - Activation of the nuclear transcription factor-kappaB (NF-kappaB) has been 
      implicated in liver tumorigenesis. We evaluated the effects of a novel NF-kappaB 
      inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in two human liver cancer cell 
      lines HA22T/VGH and HuH-6. DHMEQ treatment dose dependently decreased the 
      DNA-binding capacity of the NF-kappaB p65 subunit, inhibited cell growth and 
      proliferation, and increased apoptosis as shown by caspase activation, release of 
      cytochrome c, poly(ADP-ribose) polymerase cleavage, and down-regulation of 
      survivin. DHMEQ also induced a dose-dependent activation of mitogen-activated 
      protein kinase kinase/extracellular signal-regulated kinase signaling, and 
      inhibition of this pathway significantly reduced cell growth. It is noteworthy 
      that we observed that DHMEQ stimulated reactive oxygen species (ROS) production 
      in a dose-dependent manner and that pretreatment of the cells with the 
      antioxidant N-acetyl-L-cysteine (NAC) significantly reduced DHMEQ-induced ROS 
      generation. Accordingly, NAC completely reversed the DHMEQ-induced growth 
      inhibition, caspase activation, and cell death. DHMEQ-treated cells exhibited DNA 
      damage, as evaluated by accumulation in nuclear foci of phospho-H2AX, which was 
      completely reversed by NAC. Moreover, DHMEQ induced the expression of genes 
      involved in the endoplasmic reticulum stress response (GRP78, CHOP, TRB3) and 
      promoted the splicing of XBP1 mRNA in a dose-dependent fashion in both cell 
      lines, which was reversed in the presence of NAC. Knockdown of TRB3 mRNA 
      expression by small interference RNA significantly decreased DHMEQ-induced cell 
      growth inhibition. These data suggest that DHMEQ antitumor effects are primarily 
      mediated through ROS generation. Thereby, considering that cancer cells are under 
      increased ER stress and oxidative stress conditions, DHMEQ may greatly improve 
      various anticancer strategies.
FAU - Lampiasi, Nadia
AU  - Lampiasi N
AD  - Institute of Biomedicine and Molecular Immunology Alberto Monroy, National 
      Research Council, Palermo, Italy. lampiasi@ibim.cnr.it
FAU - Azzolina, Antonina
AU  - Azzolina A
FAU - D'Alessandro, Natale
AU  - D'Alessandro N
FAU - Umezawa, Kazuo
AU  - Umezawa K
FAU - McCubrey, James A
AU  - McCubrey JA
FAU - Montalto, Giuseppe
AU  - Montalto G
FAU - Cervello, Melchiorre
AU  - Cervello M
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090520
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Cyclohexanones)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (NF-kappa B)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (dehydroxymethylepoxyquinomicin)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Benzamides/*pharmacology
MH  - Carcinoma, Hepatocellular/genetics/metabolism/pathology
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cyclohexanones/*pharmacology
MH  - Cytochromes c/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/drug effects
MH  - Drug Evaluation, Preclinical
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - Liver Neoplasms/*drug therapy
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - NF-kappa B/*antagonists & inhibitors
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Reactive Oxygen Species/*metabolism
EDAT- 2009/05/23 09:00
MHDA- 2009/08/18 09:00
CRDT- 2009/05/23 09:00
PHST- 2009/05/23 09:00 [entrez]
PHST- 2009/05/23 09:00 [pubmed]
PHST- 2009/08/18 09:00 [medline]
AID - mol.109.055418 [pii]
AID - 10.1124/mol.109.055418 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2009 Aug;76(2):290-300. doi: 10.1124/mol.109.055418. Epub 2009 May 
      20.