Inhibition of DNA-PK enhances chemosensitivity of B-cell precursor acute lymphoblastic leukemia cells to doxorubicin

Biomed Pharmacother. 2017 Oct:94:1077-1093. doi: 10.1016/j.biopha.2017.08.022. Epub 2017 Aug 16.

Abstract

DNA damage repair pathways greatly affect the response to genotoxic drugs in cancer cells, so inhibition of such pathways could be a potentially useful strategy to enhance chemosensitivity. DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DNA double-strand breaks (DSBs) that are probably one of the most detrimental types of DNA damage. It has been shown that DNA-PK is highly expressed in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. Less well appreciated was the effect of DNA-PK inhibition on sensitivity of BCP-ALL cells to DNA-damaging agents. Here, we show that the DNA-PK inhibitor NU7441 increased doxorubicin-induced apoptosis in BCP-ALL cell lines (NALM-6, SUP-B15), correlating with a reduction in DSB repair measured by γ-H2AX foci. NU7441 affected the cell cycle distribution and the cell cycle regulatory molecules in combination with doxorubicin treatment. Doxorubicin-induced DNA-PK phosphorylation was decreased in the presence of NU7441. Apoptosis induction by the combined treatment was associated with marked reduction of Bcl-2 and survivin and a significant increase of Bax mRNA expression levels. In conclusion, our data indicate that inhibition of DNA-PK might be an effective approach to enhance the tumor-cell-killing effects of DNA-damaging agents such as doxorubicin in BCP-ALL and may deliver novel, targeted therapy into the clinic.

Keywords: Acute lymphoblastic leukemia; DNA-PK; Doxorubicin; NU7441.

MeSH terms

  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Chromones / pharmacology
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • DNA-Activated Protein Kinase / metabolism*
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Morpholines / pharmacology
  • Phosphorylation / drug effects
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism*

Substances

  • 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
  • Chromones
  • Morpholines
  • Protein Kinase Inhibitors
  • Doxorubicin
  • Protein Kinases
  • DNA-Activated Protein Kinase