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

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Summary

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.

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Acknowledgements

The authors would like to thank the staff of Peter MacCallum Bendigo Radiotherapy Centre for their support and technical assistance for irradiation of cell lines. We also would like to thank Professor Roger Martin, head of the molecular radiation biology and research division and Andrea Smith, Peter MacCallum cancer centre, Melbourne for their valuable advice and support. Suraj Radhamani was a recipient of Latrobe University Postgraduate Research scholarship (LTUPS) and Full fee Research scholarship (LTUFFRS), with additional research funding by Latrobe University.

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The authors declare that they have no conflict of interest.

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  1. School of Pharmacy and Applied Science, La Trobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia

    Suraj Radhamani, Christopher Bradley, Saleh K. Ihmaid & Jasim Al-Rawi

  2. La Trobe Rural Health School, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia

    Christopher Bradley & Terri Meehan-Andrews

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  1. Suraj Radhamani
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Correspondence to Christopher Bradley.

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Radhamani, S., Bradley, C., Meehan-Andrews, T. et al. Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair. Invest New Drugs 32, 424–435 (2014). https://doi.org/10.1007/s10637-014-0079-4

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