Abstract
Multiple myeloma is the second most common hematologic malignancy. During the pursuit for novel and more selective anticancer drugs, different approaches have pointed to polo-like kinase 1 (Plk1) as a promising target. So we used a novel agent, scytonemin, to inhibit the activity of Plk1 to investigate the effect of Plk1 in multiple myeloma cells. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to examine the effect of scytonemin on the cell proliferation of three multiple myeloma cell lines with different concentration and different time. Flow cytometry was used to examine the effect of scytonemin on the cell cycle of multiple myeloma U266 cells with different concentration and different time. Moreover, the expression of Plk1 was analyzed by Western blot and real-time PCR in myeloma U266 cells with the treatment of scytonemin. Statistical analysis was used to analyze the effect of scytonemin on the cell proliferation and cell cycle with different concentration and different time and the association between Plk1 expression and activity with the treatment of scytonemin. Scytonemin was able to inhibit the proliferation of three myeloma cells in a dose-dependent manner, while U266 was the most sensitive one to scytonemin. Treatment with 3 and 4 μM scytonemin gradually increased the percentage of cells in the G2-M phase in U266 cells upon 48- and 72-h treatment. Scytonemin (at 3 and 4 μM concentration) inhibited multiple myeloma cell growth associated with downregulation of the activity of Plk1 but no effect on the expression of Plk1. Scytonemin, representing a novel Plk1 inhibitor, induced the inhibition of cell growth and cell cycle arrest in multiple myeloma cells by specifically decreasing Plk1 activity. Taken together, scytonemin is a promising novel agent for the treatment of multiple myeloma.
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References
Cruz RD, Tricot G, Zangari M, Zhan F. Progress in myeloma stem cells. Am J Blood Res. 2011;1(2):135–45.
Lamelin JP, Vassalli P. Heterogeneity of the B cell subpopulation operationally defined by (a) differentiation antigen(s) common to MOPC 104E and mature IgM plasma cells. Immunology. 1978;35(6):885–8.
Muta T, Miyamoto T, Fujisaki T, et al. Effect of bortezomib-based induction therapy on the peripheral blood stem cell harvest in multiple myeloma. Rinsho Ketsueki. 2013;54(1):109–16.
Azarm T, Akbari M, Azarm A, Mohager H. Bortezomib in combination with low-dose oral melphalan, dexamethasone and thalidomide for relapsed elderly patients with multiple myeloma. J Res Med Sci. 2012;17(1):8–14.
Senthilkumar CS, Ganesh N. Lenalidomide-based combined therapy induced alterations in serum proteins of multiple myeloma patient: a follow-up case report and overview of the literature. Exp Oncol. 2012;34(4):373–6.
Salem K, Brown CO, Schibler J, Goel A. Combination chemotherapy increases cytotoxicity of multiple myeloma cells by modification of nuclear factor (NF)-κB activity. Exp Hematol. 2013;41(2):209–18.
Lera RF, Burkard ME. High mitotic activity of Polo-like kinase 1 is required for chromosome segregation and genomic integrity in human epithelial cells. J Biol Chem. 2012;287(51):42812–25.
Godinho S, Tavares AA. A role for Drosophila Polo protein in chromosome resolution and segregation during mitosis. Cell Cycle. 2008;7(16):2529–34.
Proteau PJ, Gerwick WH, Garcia-Pichel F, Castenholz R. The structure of scytonemin, an ultraviolet sunscreen pigment from the sheaths of cyanobacteria. Experientia. 1993;49(9):825–9.
Stevenson CS, Capper EA, Roshak AK, et al. Scytonemin—a marine natural product inhibitor of kinases key in hyperproliferative inflammatory diseases. Inflamm Res. 2002;51(2):112–4.
Zhang Z, Zhang G, Kong C. High expression of polo-like kinase 1 is associated with the metastasis and recurrence in urothelial carcinoma of bladder. Urol Oncol. 2011; [Epub ahead of print].
Zhang Z, Su WH, Feng C, et al. Polo-like kinase 1 may regulate G2-M transition of mouse fertilized eggs by means of inhibiting the phosphorylation of Tyr 15 of Cdc2. Mol Reprod Dev. 2007;74(10):1247–54.
Sato I, Abo T, Onodera S, Kumagai K. Detection of monoclonal B lymphocytes in multiple myeloma by immunofluorescence tests of surface immunoglobulins. Scand J Haematol. 1978;21(5):433–44.
Ito K, Ishikawa F, Kanno T, et al. Expression of cholesteryl ester transfer protein (CETP) in germinal centre B cells and their neoplastic counterparts. Histopathology. 2004;45(1):73–81.
Mulligan ME, Badros AZ. PET/CT and MR imaging in myeloma. Skeletal Radiol. 2007;36(1):5–16.
Maire V, Némati F, Richardson M, et al. Polo-like kinase 1: a potential therapeutic option in combination with conventional chemotherapy for the management of patients with triple-negative breast cancer. Cancer Res. 2013;73(2):813–23.
Zhao XY, Nie CL, Liang SF, Yuan Z, Deng HX, Wei YQ. Enhanced gemcitabine-mediated cell killing of human lung adenocarcinoma by vector-based RNA interference against Plk1. Biomed Pharmacother. 2012;66(8):597–602.
Luo J, Liu X. Polo-like kinase 1, on the rise from cell cycle regulation to prostate cancer development. Protein Cell. 2012;3(3):182–97.
Zhang Y, Du XL, Wang CJ, et al. Reciprocal activation between Plk1 and Stat3 contributes to survival and proliferation of esophageal cancer cells. Gastroenterology. 2012;142(3):521–30. e3.
McInnes C, Mezna M, Fischer PM. Progress in the discovery of polo-like kinase inhibitors. Curr Top Med Chem. 2005;5(2):181–97.
Renner AG, Dos Santos C, Recher C, et al. Polo-like kinase 1 is overexpressed in acute myeloid leukemia and its inhibition preferentially targets the proliferation of leukemic cells. Blood. 2009;114(3):659–62.
Morales AG, Brassesco MS, Pezuk JA, et al. BI 2536-mediated Plk1 inhibition suppresses HOS and MG-63 osteosarcoma cell line growth and clonogenicity. Anticancer Drugs. 2011;22(10):995–1001.
Liu X, Choy E, Harmon D, et al. Inhibition of polo-like kinase 1 leads to the suppression of osteosarcoma cell growth in vitro and in vivo. Anticancer Drugs. 2011;22(5):444–53.
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We thank Dr. Peter Richter (Department of Plant Ecophysiology, Friedrich-Alexander University Erlangen-Nürnberg, Germany) for presenting sytonemin as a gift.
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Zhang, G., Zhang, Z. & Liu, Z. Scytonemin inhibits cell proliferation and arrests cell cycle through downregulating Plk1 activity in multiple myeloma cells. Tumor Biol. 34, 2241–2247 (2013). https://doi.org/10.1007/s13277-013-0764-5
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DOI: https://doi.org/10.1007/s13277-013-0764-5