Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair

Invest New Drugs. 2014 Jun;32(3):424-35. doi: 10.1007/s10637-014-0079-4. Epub 2014 Mar 14.

Abstract

The DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effects of radiation. Here we present a novel benzoxazine, 8-methyl-2-(morpholine-4yl)-7-(pyridine-3-methoxy)-4H-1,3-benzoxacine-4-one (LTU27) and analyse its ability to cause sensitization of lung cancer and colon cancer cells to radiation. There was a significant reduction in survival rate, increase in apoptosis and inhibition in autophosphorylation of DNA-PK and AKT1 after treating them concomitantly with both radiation and LTU27. The mechanism of action appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Benzoxazines / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Colonic Neoplasms
  • DNA Repair / drug effects
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • Histones / metabolism
  • Humans
  • Lung Neoplasms
  • Morpholines / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Radiation-Sensitizing Agents / pharmacology*

Substances

  • 8-methyl-2-(morpholine-4-yl)-7-(pyridine-3-methoxy)-4H-1,3-benzoxacine-4-one
  • Benzoxazines
  • H2AX protein, human
  • Histones
  • Morpholines
  • Radiation-Sensitizing Agents
  • AKT1 protein, human
  • DNA-Activated Protein Kinase
  • Proto-Oncogene Proteins c-akt