Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G1 checkpoint-defective neuroblastoma

Int J Cancer. 2011 Oct 15;129(8):1953-62. doi: 10.1002/ijc.25842. Epub 2011 Mar 8.

Abstract

Checkpoint kinase inhibitors can enhance the cancer killing action of DNA-damaging chemotherapeutic agents by disrupting the S/G(2) cell cycle checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor AZD7762 when combined with these agents were examined using neuroblastoma cell lines with known p53/MDM2/p14(ARF) genomic status. Four of four p53 mutant lines and three of five MDM2/p14(ARF) abnormal lines were defective in G(1) checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA-damaging agents. In cytotoxicity assays, these G(1) checkpoint-defective lines were more resistant to DNA-damaging agents when compared to G(1) checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G(2) checkpoint arrest both in vitro and in vivo. In xenograft models, a significant delay in tumor growth accompanied by histological evidence of increased apoptosis was observed, when AZD7762 was added to the DNA-damaging drug gemcitabine. These results suggest a therapeutic potential of combination therapy using checkpoint kinase inhibitor and chemotherapy to reverse or prevent drug resistance in treating neuroblastomas with defective G(1) checkpoints.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • DNA Damage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neuroblastoma / drug therapy*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Thiophenes / pharmacology*
  • Urea / analogs & derivatives*
  • Urea / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
  • Antimetabolites, Antineoplastic
  • Protein Kinase Inhibitors
  • Thiophenes
  • Deoxycytidine
  • Urea
  • gemcitabine
  • Protein Kinases
  • Checkpoint Kinase 2
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases