title: Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways.
abstract: Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic agents. Our laboratory has recently reported that phenylhexyl isothiocyanate (PHI), a synthetic isothiocyanate, is an inhibitor of HDAC. In this study we examined whether PHI is a hypomethylating agent and its effects on myeloma cells. RPMI8226, a myeloma cell line, was treated with PHI. PHI inhibited the proliferation of the myeloma cells and induced apoptosis in a concentration as low as 0.5 muM. Cell proliferation was reduced to 50% of control with PHI concentration of 0.5 muM. Cell cycle analysis revealed that PHI caused G1-phase arrest of RPMI8226 cells. PHI induced p16 hypomethylation in a concentration- dependent manner. PHI was further shown to induce histone H3 hyperacetylation in a concentration-dependent manner. It was also demonstrated that PHI inhibited IL-6 receptor expression and VEGF production in the RPMI8226 cells, and reactivated p21 expression. It was found that PHI induced apoptosis through disruption of mitochondrial membrane potential. For the first time we show that PHI can induce both p16 hypomethylation and histone H3 hyperacetylation. We conclude that PHI has dual epigenetic effects on p16 hypomethylation and histone hyperacetylation in myeloma cells and targets several critical processes of myeloma proliferation.
authors.affiliation: Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA. Luquanyi@medmail.com.cn
authors.forename: Quanyi
authors.initials: Q
authors.lastname: Lu
authors.forename: Xianghua
authors.initials: X
authors.lastname: Lin
authors.forename: Jean
authors.initials: J
authors.lastname: Feng
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Zhao
authors.forename: Ruth
authors.initials: R
authors.lastname: Gallagher
authors.forename: Marietta Y
authors.initials: MY
authors.lastname: Lee
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Chiao
authors.forename: Delong
authors.initials: D
authors.lastname: Liu
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017879:Isothiocyanates; D019947:Receptors, Interleukin-6; D042461:Vascular Endothelial Growth Factor A; C073279:6-phenylhexyl isothiocyanate; D018631:ras Proteins