A histone deacetylase inhibitor LBH589 downregulates XIAP in mesothelioma cell lines which is likely responsible for increased apoptosis with TRAIL.
OBJECTIVE
Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a member of tumor necrosis factor family and it is important for ligand induced apoptosis in tumor cells. TRAIL has been shown to be synergistic with a variety of chemotherapies and targeted agents. In the study, a combination of TRAIL and a histone deacetylase inhibitor LBH589 was studied in mesothelioma cell lines.


METHODS
Five mesothelioma cell lines and two normal cell lines were tested for cell growth inhibition and apoptosis using high-throughput assays in the presence of LBH589, TRAIL and a combination of the two. Caspase induction was studied and levels of X-linked inhibitor of apoptosis (XIAP) were tested using Western blotting. A combination of a direct inhibitor of XIAP was also tested in combination with TRAIL.


RESULTS
In mesothelioma cell lines, a combination of LBH589 and TRAIL markedly increased cell growth inhibition and apoptosis when compared with the effect on normal cell lines. LBH589 and TRAIL appeared to induce higher levels of caspase 3 and 7 and this appeared to be closely related to ability of LBH589 to degrade XIAP. In addition, a direct inhibitor of XIAP was also sensitized cells to TRAIL apoptosis, providing an indirect confirmation for XIAP degradation as a possible mechanism of synergy.


CONCLUSIONS
In mesothelioma cell lines, LBH589 increases the sensitivity to TRAIL. In addition, at least partly, the mechanism of this induction of TRAIL sensitivity is due to LBH589 related degradation of XIAP. These results provide initial evidence for testing this combination in clinical trials.
Symanowski
James
J
Nevada Cancer Institute, Las Vegas, NV 89135, USA.
Vogelzang
Nicholas
N
Zawel
Leigh
L
Atadja
Peter
P
Pass
Harvey
H
Sharma
Sunil
S
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015151:Immunoblotting; D007211:Indoles; D007976:Leupeptins / Q000494:pharmacology; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology*; D000077767:Panobinostat; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D007976:Leupeptins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077767:Panobinostat; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde