HDAC inhibition radiosensitizes human normal tissue cells and reduces DNA Double-Strand Break repair capacity.
HDAC inhibitors (HDACi) are gaining increasing attention in the treatment of cancer, particularly in view of their therapeutic effectiveness and assumed mild toxicity profile. While numerous studies have investigated the role of HDACi in tumor cells, little is known about their effects on normal tissue cells. We studied the effect of suberoylanilide hydroxamic acid (SAHA), MS275, sodium-butyrate and valproic acid in healthy human fibroblasts and found HDACi-treatment to go along with increased radiosensitivity and reduced DSB repair capacity. In view of the potential genotoxic effects of HDACi-treatment, particularly when being administered long-term for chronic disease or when given to children, to women of childbearing age or their partners or in combination with radiotherapy, an extensive education of patients and prescribing physicians as well as a stringent definition of clinical indications is urgently required.
Purrucker
Jan C
JC
Division of Immunotherapy and Gene Therapy, Department of Internal Medicine I, José Carreras Research Center, Saarland University Medical Center, Homburg/Saar, Germany.
Fricke
Andreas
A
Ong
Mei Fang
MF
Rübe
Christian
C
Rübe
Claudia E
CE
Mahlknecht
Ulrich
U
D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008856:Microscopy, Fluorescence / Q000379:methods; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D012978:Sodium Oxybate / Q000494:pharmacology; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
D001549:Benzamides; D006877:Hydroxamic Acids; D011725:Pyridines; C118739:entinostat; D000077337:Vorinostat; D014635:Valproic Acid; D012978:Sodium Oxybate; D006655:Histone Deacetylases