Investigational New Drugs 2014-06-01

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

Suraj Radhamani, Christopher Bradley, Terri Meehan-Andrews, Saleh K Ihmaid, Jasim Al-Rawi

Index: Invest. New Drugs 32(3) , 424-35, (2014)

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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.