Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.

• Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

Histone Deacetylases: metabolism

Histones: metabolism

Histone Deacetylases: antagonists & inhibitors

Hela Cells: drug effects

Enzyme Inhibitors: pharmacology

Cyclin-Dependent Kinase Inhibitor p21: metabolism

Chromatin: ultrastructure

Chromatin: metabolism

Chromatin: drug effects

Cell Survival: drug effects

Acetylation: drug effects

Oleic Acids: pharmacology

Lactalbumin: pharmacology

Jurkat Cells: drug effects

Hydroxamic Acids: pharmacology

Publication and Content Type

art (subject category)

ref (subject category)