Research

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 Lin¹ , Jean Feng¹ , Xiangmin Zhao¹ , Ruth Gallagher¹ , Marietta Y Lee³ , Jen-Wei Chiao¹ and Delong Liu¹

¹Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA

²Department of Hematology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian Province, PR China

³Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA

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Journal of Hematology & Oncology 2008, 1:6doi:10.1186/1756-8722-1-6

Published:	9 June 2008

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 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.