title: Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair.
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.
authors.affiliation: School of Pharmacy and Applied Science, La Trobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.
authors.forename: Suraj
authors.initials: S
authors.lastname: Radhamani
authors.forename: Christopher
authors.initials: C
authors.lastname: Bradley
authors.forename: Terri
authors.initials: T
authors.lastname: Meehan-Andrews
authors.forename: Saleh K
authors.initials: SK
authors.lastname: Ihmaid
authors.forename: Jasim
authors.initials: J
authors.lastname: Al-Rawi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms; D009025:Morpholines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: C000594950:8-methyl-2-(morpholine-4-yl)-7-(pyridine-3-methoxy)-4H-1,3-benzoxacine-4-one; D048588:Benzoxazines; C468783:H2AX protein, human; D006657:Histones; D009025:Morpholines; D011838:Radiation-Sensitizing Agents; C494918:AKT1 protein, human; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt