The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells

Ringshausen, Ingo; Oelsner, Madlen; Bogner, Christian; Peschel, Christian; Decker, Thomas

doi:10.1038/sj.leu.2404922

Cited by 56 publications

(51 citation statements)

References 6 publications

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“…We observed a G 1 cell cycle arrest with corresponding changes in the expression of cell cycle regulatory proteins. These results stand in line with results from others, who have seen an induction of a G 1 arrest in mitogen-activated T lymphocytes (26) and B lymphocytes from patients with chronic lymphocytic leukemia (27). Cyclin D proteins are expressed at low levels in quiescent cells.…”

Section: Discussionsupporting

confidence: 92%

Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells

Baumann

Mandl-Weber

Völkl

et al. 2009

Molecular Cancer Therapeutics

103

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Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time-and dose-dependent manner. Annexin V-FITC/ propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2 ¶-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G 1 cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma. [Mol Cancer Ther 2009;8(2):366 -75]

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Section: Discussionsupporting

confidence: 92%

Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells

Baumann

Mandl-Weber

Völkl

et al. 2009

Molecular Cancer Therapeutics

103

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“…We have therefore investigated the antirheumatic drug A771726 known to have inhibitory effects on T lymphocytes, B lymphocytes (35), CLL cells (49) and myeloma cell lines (50). We could show that this drug induces apoptosis in CD40L/IL-4-activated, resistant CLL cells.…”

Section: Discussionmentioning

confidence: 99%

Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells

Dietrich

Krämer

Hahn

et al. 2012

Clinical Cancer Research

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Purpose: Environmental conditions in lymph node proliferation centers protect chronic lymphocytic leukemia (CLL) cells from apoptotic triggers. This situation can be mimicked by in vitro stimulation with CD40 ligand (CD40L) and interleukin 4 (IL-4). Our study investigates the impact of the drug leflunomide to overcome apoptosis resistance of CLL cells.Experimental Design: CLL cells were stimulated with CD40L and IL-4 and treated with fludarabine and the leflunomide metabolite A771726.Results: Resistance to fludarabine-mediated apoptosis was induced by CD40 activation alone stimulating high levels of BCL-XL and MCL1 protein expression. Apoptosis resistance was further enhanced by a complementary Janus-activated kinase (JAK)/STAT signal induced by IL-4. In contrast, CLL proliferation required both a CD40 and a JAK/STAT signal and could be completely blocked by pan-JAK inhibition. Leflunomide (A771726) antagonized CD40L/IL-4-induced proliferation at very low concentrations (3 mg/ mL) reported to inhibit dihydroorotate dehydrogenase. At a concentration of 10 mg/mL, A771726 additionally attenuated STAT3/6 phosphorylation, whereas apoptosis of CD40L/IL-4-activated ("resistant") CLL cells was achieved with higher concentrations (IC 50 : 80 mg/mL). Apoptosis was also effectively induced by A771726 in clinically refractory CLL cells with and without a defective p53 pathway. Induction of apoptosis involved inhibition of NF-kB activity and loss of BCL-XL and MCL1 expression. In combination with fludarabine, A771726 synergistically induced apoptosis (IC 50 : 56 mg/mL).Conclusion: We thus show that A771726 overcomes CD40L/IL-4-mediated resistance to fludarabine in CLL cells of untreated as well as clinically refractory CLL cells. We present a possible novel therapeutic principle for attacking chemoresistant CLL cells. Clin Cancer Res; 18(2); 417-31. Ó2011 AACR.

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“…Levamisole-25 mg/kg body weight 25 and leflunomide-20 mg/kg body weight 26 were used as positive controls.…”

Section: Evaluation Of Immunomodulatory Activitymentioning

confidence: 99%

Standardized Extract of Mangifera Indica L. Leaves as an Antimycobacterial and Immunomodulatory Agent

Shailajan¹,

Menon²,

Kulkarni³

et al. 2016

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Background: Mangifera indica L.; the largest fruit-tree found in India, is an important component of indigenous medical systems. Mangifera indica L. leaves (MIL) have been reported to possess various biological activities and thus, can be a useful source of substances for drug development. Although the leaves have been traditionally used as antibacterial and immunomodulatory agent, there is a paucity of scientific data in support of their efficacy. The purpose of this study was an in-depth evaluation of antimycobacterial and immunomodulatory activity of a standardized extract of MIL. Material and Methods: The hexane extract of Mangifera indica L. leaves (HEMIL) was prepared and standardized. Chromatographic characterization of HEMIL was done using validated HPLC and GC-MS/MS technique. HEMIL was evaluated for antimycobacterial and immunomodulatory activity by using various in vitro and in vivo assays. Results and Discussion: HEMIL showed lupeol and stigmasterol content of 21.04 ± 0.03 mg/g and 16.99 ± 0.04 mg/g, respectively; and total terpenoids content of 112.55 ± 2.16 mg LE/g. GC-MS/MS characterization of the extract confirmed the presence of lupeol and stigmasterol and revealed five other phytochemical constituents. The safety of HEMIL was established in vitro and in vivo. HEMIL showed concentration-dependent inhibition of MTB as evident in REMA and radiorespirometry. HEMIL was also found efficacious in immunomodulatory evaluations using RAW 264.7 cells, human PBMCs, cyclophosphamide induced myelosuppressed mice and SRBCs stimulated mice. Conclusion: The promising results not only support the traditional claim of MIL as antibacterial and immunomodulatory agent but also provide data on their use in food supplements for immuno-pharmacological use.

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The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells

Cited by 56 publications

References 6 publications

Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells

Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells

Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells

Standardized Extract of Mangifera Indica L. Leaves as an Antimycobacterial and Immunomodulatory Agent

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