Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma

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 two novel benzoxazines (LTU28 and LTU31) and analyse their ability to cause sensitization of 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 with LTU28 concomitantly with radiation. The mechanism of action by LTU28 appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis. LTU31 showed an inhibition in the phosphorylation of BRCA1, thereby blocking DNA repair by homologous recombination.