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Inhibition of AKT signalling by benzoxazine derivative LTUR6 through the modulation of downstream kinases

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Summary

Many compounds structurally similar to chromones have been developed to enhance the sensitizing effect of cancer cells to chemotherapeutic agents. Most of these compounds have been shown to promote this sensitization by targeting the repair pathways. One such compound is LTUR6, which enhances the sensitization of doxorubicin to colon cancer cells HT29, by inhibiting the phosphorylation of the double stranded break (DSB) repair enzyme AKT. The downstream regulatory targets of AKT that enhance doxorubicin mediated cytotoxicity in the presence of LTUR6 remains elusive. In this study, we performed comparative analyses of 43 kinase phosphorylation sites using the human phospho-kinase array proteome profiler. Results revealed altered expression levels of multiple proteins that regulated apoptotic signalling pathways. Increased activation of mTOR, RSK1/2/3, p38α and PRAS40 after combination treatment with LTUR6 and doxorubicin over doxorubicin alone was observed. This study provides a deeper insight into the key proteins involved and presents a novel molecular pathway.

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Fig. 1: Key proteins identified in regulating apoptotic pathway downstream to AKT.
Fig. 2: Proposed mechanism of action LTUR6.

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Acknowledgments

The authors would like to thank Dr. Jasim Al-Rawi and Rick Morrison for supplying LTUR6 compound, which was synthesized in their laboratory. The authors would like to thank Dr. Mike Angove for his constant encouragement and support.

Funding

This work was funded by Australian Postgraduate Award and LaTrobe University Postgraduate Research Scholarship (PhD fellowship to Rejitha Suraj).

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Authors and Affiliations

  1. Faculty of Science Technology and Engineering, School of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, Bendigo, Australia

    Rejitha Suraj & Christopher Bradley

  2. Hotchkiss Brain Institute and Libin Cardiovascular Institute of Alberta, Cummings School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Rejitha Suraj

  3. College of Science, Health and Engineering, La Trobe University, Bendigo, Australia

    Jasim Al-Rawi

Authors
  1. Rejitha Suraj
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  2. Jasim Al-Rawi
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  3. Christopher Bradley
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Correspondence to Rejitha Suraj.

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Suraj, R., Al-Rawi, J. & Bradley, C. Inhibition of AKT signalling by benzoxazine derivative LTUR6 through the modulation of downstream kinases. Invest New Drugs 37, 779–783 (2019). https://doi.org/10.1007/s10637-019-00726-2

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  • DOI: https://doi.org/10.1007/s10637-019-00726-2

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