title: The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells.
abstract: Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Zhang
authors.forename: Attaya
authors.initials: A
authors.lastname: Suvannasankha
authors.forename: Colin D
authors.initials: CD
authors.lastname: Crean
authors.forename: Valerie L
authors.initials: VL
authors.lastname: White
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Farag
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130
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