Novel X-linked inhibitor of apoptosis inhibiting compound as sensitizer for TRAIL-mediated apoptosis in chronic lymphocytic leukaemia with poor prognosis

Authors

  • Lukas P. Frenzel,

    1. Department I of Internal Medicine
    2. Centre of Integrated Oncology
    3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
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  • Michaela Patz,

    1. Department I of Internal Medicine
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  • Christian P. Pallasch,

    1. Department I of Internal Medicine
    2. Centre of Integrated Oncology
    3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
    4. David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
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  • Reinhild Brinker,

    1. Department I of Internal Medicine
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  • Julia Claasen,

    1. Department I of Internal Medicine
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  • Alexandra Schulz,

    1. Department I of Internal Medicine
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  • Michael Hallek,

    1. Department I of Internal Medicine
    2. Centre of Integrated Oncology
    3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
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  • Hamid Kashkar,

    1. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
    2. Institute for Medical Microbiology and Immunology, and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
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    • These authors contributed equally to this work.

  • Clemens-Martin Wendtner

    1. Department I of Internal Medicine
    2. Centre of Integrated Oncology
    3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
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    • These authors contributed equally to this work.


Lukas P. Frenzel, MD, Department I of Internal Medicine, Center for Integrated Oncology Cologne Bonn, University of Cologne, D-50937 Cologne, Germany.
E-mail: Lukas.frenzel@uk-koeln.de

Summary

Given that aggressive DNA damaging chemotherapy shows suboptimal efficacy in chronic lymphocytic leukaemia (CLL), alternative therapeutic approaches are needed. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to induce tumour-specific apoptosis. However, apoptosis might be inhibited by elevated levels of X-linked inhibitor of apoptosis (XIAP). Use of XIAP-inhibiting compounds might sensitize primary CLL cells towards TRAIL-mediated apoptosis. A novel small molecule, compound A (CA), an inhibitor of XIAP, was used in combination with TRAIL to induce apoptosis in primary CLL cells (n = 48). XIAP was significantly more highly expressed in primary CLL cells (n = 28) compared to healthy B cells (n = 16) (= 0·02). Our data obtained by specific knock-down of XIAP by siRNA identified XIAP as the key factor conferring resistance to TRAIL in CLL. Combined treatment with CA/TRAIL significantly increased apoptosis compared to untreated (= 8·5 × 10−10), solely CA (= 4·1 × 10−12) or TRAIL treated (= 4·8 × 10−10) CLL cells. CA rendered 40 of 48 (83·3%) primary CLL samples susceptible to TRAIL-mediated apoptosis. In particular, cells derived from patients with poor prognosis CLL (ZAP-70+, IGHV unmutated, 17p-) were highly responsive to this drug combination. Our highly-effective XIAP inhibitor CA, in concert with TRAIL, shows potential for the treatment of CLL cases with poor prognosis and therefore warrants further clinical investigation.

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