Medical Oncology

, 32:188 | Cite as

Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells

  • Thomas Strömberg
  • Xiaoying Feng
  • Maryam Delforoush
  • Mattias Berglund
  • Yingbo Lin
  • Magnus Axelson
  • Olle Larsson
  • Patrik Georgii-Hemming
  • Johan Lennartsson
  • Gunilla Enblad
Original Paper
First Online:
Received:
Accepted:

Abstract

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.

Keywords

Diffuse large B-cell lymphoma DLBCL Picropodophyllin PPP IGF-1R 
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Notes

Acknowledgments

This work was supported by Swedish Cancer Foundation, Swedish Research Council, European Commission Marie Curie Fellowship (EA), Cancer Society in Stockholm, Children Cancer Society, Lundberg’s Research Foundation in Gothenburg, Stockholm County Council and Karolinska Institutet.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Thomas Strömberg
    • 1
  • Xiaoying Feng
    • 2
    • 3
  • Maryam Delforoush
    • 1
  • Mattias Berglund
    • 1
  • Yingbo Lin
    • 2
  • Magnus Axelson
    • 4
  • Olle Larsson
    • 2
  • Patrik Georgii-Hemming
    • 1
  • Johan Lennartsson
    • 5
  • Gunilla Enblad
    • 1
  1. 1.Department of Immunology, Genetics and Pathology, Rudbeck LaboratoryUppsala UniversityUppsalaSweden
  2. 2.Department of Oncology-Pathology, Cancer Center KarolinskaKarolinska InstitutetStockholmSweden
  3. 3.Department of GastroenterologyThe Second Affiliated Hospital of Dalian Medical UniversityDalianPeople’s Republic of China
  4. 4.Department of Clinical ChemistryKarolinska Institutet and Karolinska University HospitalStockholmSweden
  5. 5.Ludwig Institute for Cancer ResearchUppsala UniversityUppsalaSweden

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