TY - JOUR
T1 - Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy
AU - Ronald, Sharon
AU - Awate, Sanket
AU - Rath, Abhijit
AU - Carroll, Jennifer
AU - Galiano, Floyd
AU - Dwyer, Donard
AU - Kleiner-Hancock, Heather
AU - Mathis, J. Michael
AU - Vigod, Simone
AU - De Benedetti, Arrigo
PY - 2013/3
Y1 - 2013/3
N2 - The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 and Rad9, regulating double-strand break (DSB) repair and the DNA damage response (DDR). TLKs maintain genomic stability and are important therapeutic intervention targets. We identified specific inhibitors of TLKs from several compound libraries, some of which belong to the family of phenothiazine antipsychotics. The inhibitors prevented the TLK-mediated phosphorylation of Rad9(S328) and impaired checkpoint recovery and DSB repair. The inhibitor thioridazine (THD) potentiated tumor killing with chemotherapy and also had activity alone. Staining for γ-H2AX revealed few positive cells in untreated tumors, but large numbers in mice treated with low doxorubicin or THD alone, possibly the result of the accumulation of DSBs that are not promptly repaired as they may occur in the harsh tumor growth environment.
AB - The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 and Rad9, regulating double-strand break (DSB) repair and the DNA damage response (DDR). TLKs maintain genomic stability and are important therapeutic intervention targets. We identified specific inhibitors of TLKs from several compound libraries, some of which belong to the family of phenothiazine antipsychotics. The inhibitors prevented the TLK-mediated phosphorylation of Rad9(S328) and impaired checkpoint recovery and DSB repair. The inhibitor thioridazine (THD) potentiated tumor killing with chemotherapy and also had activity alone. Staining for γ-H2AX revealed few positive cells in untreated tumors, but large numbers in mice treated with low doxorubicin or THD alone, possibly the result of the accumulation of DSBs that are not promptly repaired as they may occur in the harsh tumor growth environment.
KW - DNA damage response
KW - inhibitors of Tousled kinases
KW - mechanism of DSB repair
KW - radiomimetic sensitizers
UR - http://www.scopus.com/inward/record.url?scp=84887442317&partnerID=8YFLogxK
U2 - 10.1177/1947601913479020
DO - 10.1177/1947601913479020
M3 - Article
C2 - 23946870
AN - SCOPUS:84887442317
SN - 1947-6019
VL - 4
SP - 39
EP - 53
JO - Genes and Cancer
JF - Genes and Cancer
IS - 1-2
ER -