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Histone Deacetylase Inhibitors Promote the Tumoricidal Effect of HAMLET

¹ Institute of Laboratory Medicine, Section of Microbiology, Immunology, and Glycobiology, Lund University; ² AstraZeneca R&D, Lund, Sweden; and ³ Institut Andre Lwoff, CNRS UPR9079, Equipe Fonction et Dynamique de la Chromatine, Villejuif, France

Requests for reprints: Catharina Svanborg, Institute of Laboratory Medicine, Section of Microbiology, Immunology, and Glycobiology, Lund University, Sölvegatan 23, SE-22362 Lund, Sweden. Phone: 46-709-426549; Fax: 46-46-137468; E-mail: Catharina.Svanborg{at}med.lu.se.

Histone deacetylase inhibitors (HDIs) and HAMLET (human -lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo. [Cancer Res 2007;67(23):11327–34]