Piperlongumine inhibits proliferation and survival of Burkitt lymphoma in vitro

• Type of Material: Article
• Authors: Dongju Son, Emory University; Seong-Su Han, University of Iowa; Hwakyung Yun, Hanseo University; Natalie L. Kamberos, University of Iowa; Siegfried Janz, University of Iowa
• Language: English
• Date: 2013-02-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.leukres.2012.11.009
• Title of Journal or Parent Work: Leukemia Research
• Volume: 37
• Issue: 2
• Start Page: 146
• End Page: 154
• Grant/Funding Information: This work was also supported, in part, by research awards from the International Waldenström’s Macroglobulinemia Foundationa nd R01CA151354 from the NCI.; This work was supported in part by Korea Research Foundation Grant KRF-2007–357-E00032 provided to DJS by the Korean Government (MOEHRD).
• Keywords: NF-kappa B; Proto-Oncogene Proteins c-myc; Burkitt Lymphoma; Gene Expression Regulation, Neoplastic; E2F1 Transcription Factor; Enzyme Activation; Antigens, Differentiation; Inhibitory Concentration 50; Dioxolanes; Genes, myb; Cell Line, Tumor; Apoptosis; Cell Proliferation; Viral Matrix Proteins; Humans; Antineoplastic Agents; Caspase 3; Cell Survival
• Research Categories: Chemistry, Biochemistry; Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Piperlongumine (PL), a pepper plant alkaloid from Piper longum, kills solid tumor cells in a highly selective, potent fashion. To evaluate whether PL may have similar effects on malignant blood cells, we determined the efficacy with which PL inhibits the B-lymphocyte derived neoplasm, Burkitt lymphoma (BL). Low micromolar concentrations of PL (IC50=2.8μM×8.5μM) curbed growth and survival of two EBV+ BL cell lines (Daudi, Raji) and two EBV BL cell lines (Ramos, DG-75), but left normal peripheral blood B-lymphocytes unharmed. PL-dependent cytotoxicity was effected in part by reduced NF-κB and MYC activity, with the former being caused by inhibition of IκBα degradation, nuclear translocation of p65, and binding of NF-κB dimers to cognate DNA sequences in gene promoters. In 4 of 4 BL cell lines, the NF-κB/MYC-regulated cellular target genes, E2F1 and MYB, were down regulated, while the stress sensor gene, GADD45B, was up regulated. The EBV-encoded oncogene, LMP-1, was suppressed in Daudi and Raji cells. Considering that NF-κB, MYC and LMP-1 play a crucial role in the biology of many blood cancers including BL, our results provide a strong preclinical rationale for considering PL in new intervention approaches for patients with hematologic malignancies.