Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways

Journal of Hematology & Oncology, Jun 2008

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 μM. Cell proliferation was reduced to 50% of control with PHI concentration of 0.5 μM. 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.

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Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways

Journal of Hematology & Oncology Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways Quanyi Lu 1 2 Xianghua Lin 2 Jean Feng 2 Xiangmin Zhao 2 Ruth Gallagher 2 Marietta Y Lee 0 Jen-Wei Chiao 2 Delong Liu 2 0 Department of Biochemistry and Molecular Biology, New York Medical College , Valhalla, NY 10595 , USA 1 Department of Hematology, Zhongshan Hospital of Xiamen University , Xiamen, Fujian Province , PR China 2 Division of Hematology/Oncology, New York Medical College , Valhalla, NY 10595 , USA 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 M. Cell proliferation was reduced to 50% of control with PHI concentration of 0.5 M. 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. - Background Despite many recent advances in treatment, multiple myeloma (MM) remains as an incurable disease without an allogeneic hematopoietic cell transplantation. The emergence of drug resistance and incomplete responses have been the major obstacles for improving the treatment results [1,2]. The new treatment strategies have been based largely upon targeting specific molecules or pathways, such as proteosome inhibitors and thalidomide analogs. Aberrant methylation of gene promoter regions is a widely studied epigenetic process in malignant disorders. Cell cycle inhibitors of p15 and p16 are the tumor suppressor genes frequently affected by this epigenetic change [3,4]. The aberrant methylation of gene promoter regions is associated with loss of gene function. In addition to gene deletions and mutations, quantitative changes in gene methylation status play a significant role in tumorigenesis [5]. Hypermethylation of p15 and p16 promoter CpG islands has been reported in MM clinical specimens and myeloma cell lines [4,6,7]. The methylation status of p15 and p16 genes were not significantly different between MM and MGUS (monoclonal gammopathy of unknown significance) nor in pre-treated and post-treated patients with MM [6-8]. It was further demonstrated in MM patients that p16 hypermethylation is associated with high plasma cell proliferation, higher 2-microglobulin concentration, and shorter survival, whereas no such clear correlation was found with p15 CpG island hypermethylation [4,7,9]. The proliferation and survival of myeloma cells are also potentiated by IL-6 and IL-6 receptor signal transduction through autocrine and paracrine stimulation [10,11]. Exogenous IL-6 was able to block the apoptosis induced by the chemotherapeutic agent dexamethasone [10,12]. Increased angiogenesis and microvascular density in the bone marrow microenvironment correlate with poor prognosis and drug resistance of myeloma cells [13-15]. Cytokines that augment angiogenesis are known to be present at elevated levels in the bone marrow. The vascular endothelial growth factor (VEGF) is one of those elevated cytokines associated with angiogenesis. Thalidomide and its derivative, lenalidomide (CC-5013, Revlimid; Celgene), are inhibitors of angiogenesis and are widely used for MM therapy [1]. In the search for novel molecular targets, histone deacetylases (HDACs) that affect epigenetic processes have emerged as one of the potential targets [16,17]. Recent studies have indicated that the expression of various genes that regulate differentiation, proliferation, and apoptosis are also influenced by HDACs. Aberrant histone acetylation appears to play an important role in the development of numerous malignancies [18,19]. Agents that modify histone acetylation thus show great promise against various malignancies [20-26]. Vorinostat (Suberoylanilide hydroxamic acid, SAHA, Zolinza; Merck) is among the first HDAC inhibitors approved for clinical treatment of cutaneous T cell lymphoma [27,28]. Our laboratory has (...truncated)


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Quanyi Lu, Xianghua Lin, Jean Feng, Xiangmin Zhao, Ruth Gallagher, Marietta Y Lee, Jen-Wei Chiao, Delong Liu. Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways, Journal of Hematology & Oncology, 2008, pp. 6, 1, DOI: 10.1186/1756-8722-1-6