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Inhibition of the 19 S proteasome by bAP-15 in lymphoma cell lines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Inhibition of activity of proteasome by bortezomib has been shown to selectively kill cancer cells. Bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma and the proteolytic 20S core particle of the proteasome, has also been clinically validated as a therapeutic target in oncology. However, despite its acceptable therapeutic index, patients treated with bortezomib show toxic side effects and eventually acquire resistance to the drug. A lot of efforts are currently been made to develop new proteasome inhibitors that perform through mechanisms different from that of bortezomib.

We have studied the effects of b-AP15, a novel inhibitor of the deubiquitinase activity in the 19S regulatory subunit of the proteasome, on a panel of nine cell-lines from diffuse large B-cell lymphomas (DLBCL) and three from Hodgkin lymphoma (HL). All cell lines showed a dose dependent reduction of viability. The inhibition of the 19S subunit by b-AP15 resulted, as expected, in accumulation of ubiquitinylated proteins at concentrations close to cytotoxic IC50. Increases in polyubiquitinated proteins were paralleled by increases in the inducible form of heat shock protein 70 (Hsp70B´), and a strong association between Hsp70B´ induction and cleavage of PARP and caspase-3 was observed. These data suggest that proteotoxic stress mediates the sensitivity of lymphoma cells to the deubiquitinase inhibitor b-AP15.

The findings in this study suggest that b-AP15 should further evaluated as a drug in lymphoma treatment.

National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-280537OAI: oai:DiVA.org:uu-280537DiVA: diva2:911135

Maryam Delforoush and Chao Sun contributed equally.

Available from: 2016-03-11 Created: 2016-03-11 Last updated: 2016-04-21Bibliographically approved
In thesis
1. Potential New Drugs in Lymphoma
Open this publication in new window or tab >>Potential New Drugs in Lymphoma
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lymphomas are malignant tumours arising from cells in the lymphatic system. They are classified as B-cell lymphomas, T-cell lymphomas and Hodgkin lymphoma (HL). Of the B-cell lymphomas, one of the most common is diffuse large B-cell lymphoma (DLBCL). Many patients with lymphomas can be successfully treated however patients who relapse or are refractory have a poor prognosis, warranting further investigations to identify potential targets and develop novel drugs.

Picropodophyllin (PPP), a potent and selective inhibitor of IGF-1R, inhibits malignant cell growth with low or no toxicity on normal cells in preclinical models. In paper I, we investigated the potential benefits of using PPP against DLBCL and found that the anti-tumor effects of PPP might possibly be explained by IGF-1R-unrelated mechanism(s). However, the inhibitory effects of PPP on lymphoma cells together with its low toxicity in vivo makes it a promising drug candidate for treatment. Melflufen, a derivative of melphalan, is currently being evaluated in a clinical phase I/II trial in relapsed or refractory multiple myeloma. In paper II, we confirmed previous reports of superior potency of melflufen over melphalan. Being active in cell lines and primary cultures of lymphoma cells as well as in a xenograft model in mice, melflufen considered being a candidate for further evaluation in treatment. bAP-15, a novel inhibitor of proteasome activity, inhibits ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase L5 (UCHL5). In paper III, we investigated the activity of b-AP15 in DLBCL and HL cell lines and compared the results to standard drugs used in treatment. Results showed inhibition of the proteasome and growth inhibition/cytotoxicity with IC50-values in the micromolar range. Treatment failure and lack of clinical benefit of proteasome inhibitors like bortezomib in DLBCL patients inspired us investigating for possible new targets, with major focus on proteasome inhibitors in DLBCL. In paper IV, we suggested that UCHL5 and/or USP14, as new targets for proteasome inhibitors in DLBCL, be further evaluated.

The findings in this thesis suggest that PPP, Melflufen and b-AP15 are potential candidates for clinical drug development and UCHL5 and/or USP14 are new potential targets for proteasome inhibitors in DLBCL.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 60 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1200
lymphoma, diffuse large B-cell lymphoma, DLBCL, picropodophyllin, PPP, J1, melflufen, prodrug, cancer therapeutics, alkylating agents, b-AP15, proteasome inhibitors, DUB inhibition, UCHL5, USP14
National Category
Medical and Health Sciences Cancer and Oncology
urn:nbn:se:uu:diva-280546 (URN)978-91-554-9524-4 (ISBN)
Public defence
2016-05-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Available from: 2016-04-20 Created: 2016-03-11 Last updated: 2016-04-21

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