Open Access

The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL‑induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells

  • Authors:
    • Seema-Maria Nathwani
    • Lisa M. Greene
    • Stefania Butini
    • Giuseppe Campiani
    • D. Clive Williams
    • Afshin Samali
    • Eva Szegezdi
    • Daniela M. Zisterer
  • View Affiliations

  • Published online on: May 12, 2016     https://doi.org/10.3892/ijo.2016.3518
  • Pages: 74-88
  • Copyright: © Nathwani et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Apoptotic defects are frequently associated with poor outcome in pediatric acute lymphoblastic leukaemia (ALL) hence there is an ongoing demand for novel strategies that counteract apoptotic resistance. The death ligand TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) and its selective tumour receptor system has attracted exceptional clinical interest. However, many malignancies including ALL are resistant to TRAIL monotherapy. Tumour resistance can be overcome by drug combination therapy. TRAIL and its agonist antibodies are currently undergoing phase II clinical trials with established chemotherapeutics. Herein, we present promising therapeutic benefits in combining TRAIL with the selective anti-leukaemic agents, the pyrrolo-1,5-benzoxazepines (PBOXs) for the treatment of ALL. PBOX-15 synergistically enhanced apoptosis induced by TRAIL and a DR5-selective TRAIL variant in ALL-derived cells. PBOX-15 enhanced TRAIL-induced apoptosis by dual activation of extrinsic and intrinsic apoptotic pathways. The specific caspase-8 inhibitor, Z-IETD-FMK, identified the extrinsic pathway as the principal mode of apoptosis. We demonstrate that PBOX-15 can enhance TRAIL-induced apoptosis by upregulation of DR5, reduction of cellular mitochondrial potential, activation of the caspase cascade and downregulation of PI3K/Akt, c-FLIP, Mcl-1 and IAP survival pathways. Of note, the PI3K pathway inhibitor LY-294002 significantly enhanced the apoptotic potential of TRAIL and PBOX-15 validating the importance of Akt downregulation in the TRAIL/PBOX-15 synergistic combination. Considering the lack of cytotoxicity to normal cells and ability to downregulate several survival pathways, PBOX-15 may represent an effective agent for use in combination with TRAIL for the treatment of ALL.
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July-2016
Volume 49 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Nathwani S, Greene LM, Butini S, Campiani G, Williams DC, Samali A, Szegezdi E and Zisterer DM: The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL‑induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells. Int J Oncol 49: 74-88, 2016
APA
Nathwani, S., Greene, L.M., Butini, S., Campiani, G., Williams, D.C., Samali, A. ... Zisterer, D.M. (2016). The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL‑induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells. International Journal of Oncology, 49, 74-88. https://doi.org/10.3892/ijo.2016.3518
MLA
Nathwani, S., Greene, L. M., Butini, S., Campiani, G., Williams, D. C., Samali, A., Szegezdi, E., Zisterer, D. M."The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL‑induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells". International Journal of Oncology 49.1 (2016): 74-88.
Chicago
Nathwani, S., Greene, L. M., Butini, S., Campiani, G., Williams, D. C., Samali, A., Szegezdi, E., Zisterer, D. M."The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL‑induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells". International Journal of Oncology 49, no. 1 (2016): 74-88. https://doi.org/10.3892/ijo.2016.3518