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The novel pyrrolo-1,5-benzoxazepine, PBOX-15, synergistically enhances the apoptotic efficacy of imatinib in gastrointestinal stromal tumours; suggested mechanism of action of PBOX-15

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Summary

The C-KIT receptor tyrosine kinase is constitutively activated in the majority of gastrointestinal stromal tumours (GIST). Imatinib (IM) a selective inhibitor of C-KIT, is indicated for the treatment of KIT-positive unresectable and/or metastatic GIST, and has tripled the survival time of patients with metastatic GIST. However, the majority of patients develop IM-resistance and progress. Although IM elicits strong antiproliferative effects, it fails to induce sufficient levels of apoptosis; acquired IM-resistance and disease recurrence remain an issue, a more effective drug treatment is greatly needed. We examined the effect of a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-15 in combination with IM on GIST cells. PBOX-15 decreased viability and in combination with IM synergistically enhanced apoptosis in both IM-sensitive and IM-resistant GIST cells, decreased the anti-apoptotic protein Mcl-1, and enhanced activation of pro-caspase-3 and PARP cleavage. The combination treatment also led to an enhanced inhibition of C-KIT-phosphorylation and inactivation of C-KIT-dependent signalling in comparison to either drug alone; CDC37, a key regulator of C-KIT in GIST was also dramatically decreased. Furthermore, PBOX-15 reduced CKII expression, an enzyme which regulates the expression of CDC37. In conclusion, our findings indicate the potential of PBOX-15 to improve the apoptotic response of IM in GIST cells and provide a more effective treatment option for GIST patients.

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Acknowledgments

We would like to thank Novartis Pharma AG, Basel, Switzerland for their kind donation of imatinib. We would also like to thank Dr. Jonathan Fletcher for his initial advice with this project.

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Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland

    Paula Kinsella, Lisa M. Greene, Sandra A. Bright, Jade K. Pollock, D. Clive Williams & Daniela M. Zisterer

  2. European Research Centre for Drug Discovery & Development, DBCF, University of Siena, Siena, Italy

    Stefania Butini & Giuseppe Campiani

  3. West German Cancer Center, Medical Oncology, Essen, Germany

    Sebastian Bauer

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  1. Paula Kinsella
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  2. Lisa M. Greene
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Correspondence to Paula Kinsella.

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Supp Fig.1

Imatinib/PBOX-15 gives a small amount of PARP cleavage in GIST-T1. Cells were treated with vehicle (Veh), imatinib (0.16 μM), PBOX-15 (0.6 μM) or combination for 24 h in GIST-T1 cells, cell lysates were prepared for western blot analysis. β-actin expression was measured as a loading control. Results are representative of three separate experiments. (PPTX 126 kb)

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Kinsella, P., Greene, L.M., Bright, S.A. et al. The novel pyrrolo-1,5-benzoxazepine, PBOX-15, synergistically enhances the apoptotic efficacy of imatinib in gastrointestinal stromal tumours; suggested mechanism of action of PBOX-15. Invest New Drugs 34, 159–167 (2016). https://doi.org/10.1007/s10637-016-0331-1

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  • DOI: https://doi.org/10.1007/s10637-016-0331-1

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