uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
Visa övriga samt affilieringar
2015 (Engelska)Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, nr 7, artikel-id 188Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP-AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by inhibition of proliferation. Pretreatment of U-2932 or U-2940 cell lines with PPP at biologically active concentrations did not prevent ligand-induced phosphorylation of IGF-1R at Tyr1131/1136 or its downstream targets AKT and ERK1/2. In contrast, the IGF-1R inhibitor NVP-AEW541 clearly inhibited phosphorylation of IGF-1R and AKT, while ERK1/2 phosphorylation was less affected. Taken together, the inhibitory effects of PPP in DLBCL cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease. However, we suggest that the primary target of PPP in these cells is not related to inhibition of IGF-1R phosphorylation.

Ort, förlag, år, upplaga, sidor
2015. Vol. 32, nr 7, artikel-id 188
Nyckelord [en]
Diffuse large B-cell lymphoma, DLBCL, Picropodophyllin, PPP, IGF-1R
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:uu:diva-256985DOI: 10.1007/s12032-015-0630-yISI: 000355619300007OAI: oai:DiVA.org:uu-256985DiVA, id: diva2:838704
Tillgänglig från: 2015-07-01 Skapad: 2015-06-29 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
Ingår i avhandling
1. Potential New Drugs in Lymphoma
Öppna denna publikation i ny flik eller fönster >>Potential New Drugs in Lymphoma
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 60
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1200
Nyckelord
lymphoma, diffuse large B-cell lymphoma, DLBCL, picropodophyllin, PPP, J1, melflufen, prodrug, cancer therapeutics, alkylating agents, b-AP15, proteasome inhibitors, DUB inhibition, UCHL5, USP14
Nationell ämneskategori
Medicin och hälsovetenskap Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-280546 (URN)978-91-554-9524-4 (ISBN)
Disputation
2016-05-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-04-20 Skapad: 2016-03-11 Senast uppdaterad: 2016-04-21

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltext

Personposter BETA

Delforoush, MaryamBerglund, MattiasLennartsson, JohanEnblad, Gunilla

Sök vidare i DiVA

Av författaren/redaktören
Delforoush, MaryamBerglund, MattiasLennartsson, JohanEnblad, Gunilla
Av organisationen
Institutionen för immunologi, genetik och patologiExperimentell och klinisk onkologiLudwiginstitutet för cancerforskning
I samma tidskrift
Medical Oncology
Cancer och onkologi

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 650 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf