Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy

Sharon Ronald, Sanket Awate, Abhijit Rath, Jennifer Carroll, Floyd Galiano, Donard Dwyer, Heather Kleiner-Hancock, James Michael Mathis, Simone Vigod, Arrigo De Benedetti

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)39-53
Number of pages15
JournalGenes and Cancer
Volume4
Issue number1-2
DOIs
StatePublished - 1 Mar 2013

Fingerprint

DNA Damage
Phosphotransferases
Thioridazine
Neoplasms
Therapeutics
Chromatin Assembly and Disassembly
Genomic Instability
DNA Repair
Doxorubicin
Antipsychotic Agents
Libraries
phenothiazine
Phosphorylation
Staining and Labeling
Drug Therapy
Growth
Genes

Keywords

  • DNA damage response
  • inhibitors of Tousled kinases
  • mechanism of DSB repair
  • radiomimetic sensitizers

Cite this

Ronald, Sharon ; Awate, Sanket ; Rath, Abhijit ; Carroll, Jennifer ; Galiano, Floyd ; Dwyer, Donard ; Kleiner-Hancock, Heather ; Mathis, James Michael ; Vigod, Simone ; De Benedetti, Arrigo. / Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy. In: Genes and Cancer. 2013 ; Vol. 4, No. 1-2. pp. 39-53.
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Ronald, S, Awate, S, Rath, A, Carroll, J, Galiano, F, Dwyer, D, Kleiner-Hancock, H, Mathis, JM, Vigod, S & De Benedetti, A 2013, 'Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy', Genes and Cancer, vol. 4, no. 1-2, pp. 39-53. https://doi.org/10.1177/1947601913479020

Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy. / Ronald, Sharon; Awate, Sanket; Rath, Abhijit; Carroll, Jennifer; Galiano, Floyd; Dwyer, Donard; Kleiner-Hancock, Heather; Mathis, James Michael; Vigod, Simone; De Benedetti, Arrigo.

In: Genes and Cancer, Vol. 4, No. 1-2, 01.03.2013, p. 39-53.

Research output: Contribution to journalArticleResearchpeer-review

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