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Inhibition of bortezomib-induced apoptosis by red blood cell uptake

Leukemia volume 20, pages 1646–1649 (2006)Cite this article

Bortezomib (also known as PS-341; VELCADE) is a reversible proteasome inhibitor that selectively blocks the chymotryptic activity of the 26S proteasome.1 Although the exact mechanism of action of bortezomib remains unclear, proteasome inhibitors are known to increase the activity and accumulation of proapoptotic, and suppress antiapoptotic molecules. Bortezomib has been identified as an attractive candidate for tumor therapy because it may overcome drug resistance in many malignancies.

Chronic lymphocytic leukemia (CLL) is an incurable disease. Novel, effective therapeutic agents are urgently required. Bortezomib may have therapeutic potential in CLL.1, 2 However, despite significant apoptotic activity of bortezomib in CLL cells in vitro at nanomolar levels, including those with resistance to fludarabine,1, 2 there have been no reports of comparable activity in vivo. Preliminary results on a small number of patients with relapsed or resistant CLL were disappointing.3, 4 Given the sensitivity of CLL to bortezomib in vitro, the lack of significant activity in vivo was unanticipated. We have confirmed that bortezomib is highly potent at inducing apoptosis at nanomolar concentrations in all CLL patient samples, irrespective of IGHV mutation status or fludarabine resistance (Table 1). Furthermore, we show that uptake of bortezomib by red blood cells (RBCs) may be a significant contributory factor in the observed lack of activity in CLL patients in vivo. Different dosing schedules may be required to address this problem.

Table 1 Summary of data from 46 patients with CLL
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Acknowledgements

We thank Millennium Pharmaceuticals Inc., Cambridge, MA, USA for providing bortezomib. Bioanalysis of bortezomib concentrations were conducted at Tandem Laboratories, NJ, USA. Pharmacokinetic analysis was carried out by Mrs Christina Pligavko, Development DMPK group at Millennium Pharmaceuticals Inc., Cambridge, MA, USA. This work was supported by the Medical Research Council.

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  1. Department of Hematology, MRC Toxicology Unit, University of Leicester, Leicester, UK

    L M C Wheat, S L Kohlhaas, A Majid, R J Walewska & M J S Dyer

  2. Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium

    J Monbaliu & R De Coster

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  1. L M C Wheat
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  2. S L Kohlhaas
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  3. J Monbaliu
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  7. M J S Dyer
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Correspondence to M J S Dyer.

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Wheat, L., Kohlhaas, S., Monbaliu, J. et al. Inhibition of bortezomib-induced apoptosis by red blood cell uptake. Leukemia 20, 1646–1649 (2006). https://doi.org/10.1038/sj.leu.2404290

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