Abstract
Aim:
Wilms' tumor1 (WT1) gene is highly expressed in leukemic blast cells of myeloid and lymphoid origin. Thus, WT1 mRNA and protein serve as promising tumor markers for the detection of leukemia and monitoring of disease progression. The purpose of this study was to investigate the modulating effects of curcumin on WT1 gene expression in the human leukemic cell line K562.
Methods:
The cytotoxicity of curcumin on the K562 cell line was evaluated by using 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The K562 cell line was treated with a non-cytotoxic dose of curcumin (5,10, or 15 μmol/L) for 13 d. The expression levels of WT1 protein and WT1 mRNA were assessed by Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR), respectively.
Results:
Curcumin had a cytotoxic effect on K562 leukemic cells with an inhibitory concentration at 50% (IC50) of approximately 20 μg/mL (54.3 μmol/L). Non-cytotoxic doses of curcumin, at concentrations of 5,10, and 15 μmol/L for 2 d, decreased the level of WT1 protein and WT1 mRNA in the K562 cell line in a dose-dependent manner. Similarly, curcumin at a concentration of 10 μmol/L significantly decreased the level of WT1 protein and mRNA in a time-dependent manner.
Conclusion:
The inhibitory effects of curcumin are associated with a decrease in the levels of both WT1 protein and WT1 mRNA. The current study provides a molecular basis for future clinical trials in leukemic patients. Thus, curcumin could be a promising chemotherapeutic agent for human leukemia.
Similar content being viewed by others
Article PDF
References
Fraizer GC, Patmasiriwat P, Zhang XH, Saunders GF . Expression of the tumor suppressor gene WT1 in both human and mouse bone marrow. Blood 1995; 86: 4704–6.
Patmasiriwat P, Fraizer GC, Claxton D, Kantarjian H, Saunders GF . Expression of WT1 and GATA-1 in AML with chromosome 16q22 abnormalities. Leukemia 1996; 10: 1127–33.
Osborne D, Frost L, Tobal K, Liu Yin JA . Elevated levels of WT1 transcripts in bone marrow harvests are associated with a high relapse risk in patients autografted for acute myeloid leukemia. Bone Marrow Transplant 2005; 36: 67–70.
Olszewski M, Muang W, Chou PM, Duerst R, Kletzel M . Wilms' tumor1 (WT1) gene in hematopoiesis: a surrogate marker of cell proliferation as a possible mechanism of action? Cytotherapy 2005; 7: 57–61.
Kelley TW, Huntsman D, McNagny KM, Roskelley CD, Hsi ED . Podocalyxin: a marker of blasts in acute leukemia. Am J Clin Pathol 2005; 124: 134–42.
Keilholz U, Menssen HD, Gaiger A, Menke A, Oji Y, Oka Y, et al. Wilms' tumour 1 (WT1) in human neoplasia. Leukemia 2005; 19: 1318–23.
Barragan E, Cervera J, Bolufer P, Ballester S, Martin G, Fernandez P, et al. Prognostic implications of Wilms' tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 2004; 89: 926–33.
Bai B, Wang HW, Xu YQ, Yang HN, Qiao ZH . Fluorescence quantitative PCR detection of WT1 gene expression in peripheral blood of patients with acute leukemias and its clinical implication. Chin J Exp Hematol 2005; 13: 610–4. Chinese.
Svensson E, Eriksson H, Gekas C, Olofsson T, Richter J, Gullberg U . DNA-binding dependent and independent functions of WT1 protein during human hematopoiesis. Exp Cell Res 2005; 308: 211–21.
Phelan SA, Lindberg C, Call KM . Wilms' tumor gene, WT1, mRNA is down-regulated during induction of erythroid and mega-karyocytic differentiation of K562 cells. Cell growth Differ 1994; 5: 677–86.
Sekiya M, Adachi M, Hinoda Y, Imai K, Yachi A . Down-regulation of Wilms' tumor gene (WT1) during myelomonocytic differentiation in HL60 cells. Blood 1994; 83: 1876–82.
Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M, et al. Growth inhibition of human leukemic cells by WT1 (Wilms' tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 1996; 87: 2878–84.
Miwa H, Beran M, Saunders GF . Expression of Wilms' tumor gene in human leukemias. Leukemia 1992; 6: 405–9.
Miyaki T, Ahuji H, Kubota T, Kubonishi I, Koeffler HP, Miyoshi I . Expression of candidate Wilms' tumor gene, WT1, in human leukemia cells. Leukemia 1993; 7: 970–7.
Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H, et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–9.
Sugiyama H . Wilms' tumor gene WT1: oncogenic function and clinical application. Int J Hematol 2001; 73: 177–87.
Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E, et al. High level of Wilms' tumor gene (WT) mRNA in acute myeloid leukemia are associated with a worse long-term outcome. Blood 1997; 90: 1217–25.
Govindarajan VS . Turmeric: chemistry, technology and quality. CRC Crit Rev Food Sci Nutr 1990; 12: 199–301.
Ammon HPT, Wahl MA . Pharmacology of Curcuma longa. Planta Med 1991; 57: 1–7.
Kunchandy E, Rao MNA . Oxygen radical scavenging activity of curcumin. Int J Pharm 1990; 58: 237–40.
Soudamini KK, Kuttan R . Inhibition of chemical carcinogenesis by curcumin. J Ethnopharmacol 1989; 27: 227–33.
Kuo ML, Huang TS, Lin JK . Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. Biochim Biophys Acta 1996; 1317: 95–100.
Nagabhushan M, Amonkar AJ, Bhide SV . In vitro antimutagenicity of curcumin against environmental mutagens. Food Chem Toxicol 1987; 25: 545–7.
Rao CV, Rivenson A, Simi B, Reddy BS . Chemoprevention of colon cancer by dietary curcumin. Ann NY Acad Sci 1995; 768: 201–4.
Limtrakul P, Lipigorngoson S, Namwong O, Apisariyakul A, Dunn FW . Inhibitory effect of dietary curcumin on skin carcinogenesis in mice. Cancer Lett 1997; 116: 197–203.
Limtrakul P, Anuchapreeda S, Lipigorngoson S, Dunn FW . Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin. BMC Cancer 2001; 1: 1–7.
Rao DS, Sekhara NC, Satyanarayana MN, Srinivasan M . Effect of curcumin on serum and liver cholesterol levels in the rat. J Nutr 1970; 100: 1307–15.
Srinivasan M . Effect of curcumin on blood sugar as seen in a diabetic subject. Indian J Med Sci 1972; 26: 269–70.
Anuchapreeda S, Leechanachai P, Smith M, Ambudkar SV, Limtrakul P . Modulation of P-glycoprotein expression and function by curcumin in Multidrug resistant human KB cells. Biochem Pharmacol 2002; 64: 573–82.
Qureshi S, Shah AH, Ageel AM . Toxicity studies on Alpinia galanga and Curcuma longa. Planta Medica 1992; 58: 124–7.
Shankar TN, Shantha NV, Ramesh HP, Murthy IA, Murthy VS . Toxicity studies on Turmeric: acute toxicity studies in rats, guinea pigs and monkeys. Indian J Exp Biol 1980; 18: 73–5.
Alley MC, Scudiero DA, Monks A . Feasibility of drug screening with panels of human tumour cell lines using a microculture tetrazolium assay. Cancer Res 1988; 48: 589–01.
Limtrakul P, Chearwae W, Leukumharn S . Inhibitory effect of curcumin on TPA (12-O-tetradecanoyl phorbol-13-acetate)-induced activation of protein kinase C isoenzyme-epsilon and c-fos protein level in human keratinocytes. Science Asia 2005; 31: 113–20.
Oji Y, Ogawa H, Tamaki H, Oka Y, Tsuboi A, Kim EH, et al. Expression of Wilms' tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Jpn J Cancer Res 1999; 90: 194–204.
Ye Y, Raychaudhuri B, Gurney A, Campbell CE, Williams BR . Regulation of WT1 by phosphorylation: inhibition of DNA binding, alteration of transcriptional activity and cellular translation. EMBO J 1996; 15: 5606–15.
Chen WH, Chen Y, Gu JX, He J . Effect of curcumin on STAT5 signaling molecule in K562 cells. Chin J Hematol 2004; 25: 151–3.
Wu YJ, Fraizer DC, Suanders GF . GATA-1 transactivates the WT1 hematopoietic specific enhancer. J Biol Chem 1995; 270: 5944–9.
Limtrakul P, Chearwae W, Anuchapreeda S . The effect of curcumin on the proliferation of cancer cell lines. Chiang Mai Med Bull 1999; 38: 55–61.
Liu HL, Chen Y, Cui GH, Zhou JF . Curcumin, a potent anti-tumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation. Acta Pharmacol Sin 2005; 26: 603–9.
Dovoix A, Morcean F, Delhalle S, Schmitz M, Schnekenburger, Galteau MM, et al. Inhibition of apoptosis by curcumin mediation by glutathione S-transferase P1-1 inhibition. Biochem Pharmacol 2003; 66: 1475–83.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by grants from the Thailand Research Fund, the Commission of Higher Education and Faculty of Associated Medical Sciences Endowment Fund.
Rights and permissions
About this article
Cite this article
Anuchapreeda, S., Thanarattanakorn, P., Sittipreechacharn, S. et al. Curcumin inhibits WT1 gene expression in human leukemic K562 cells. Acta Pharmacol Sin 27, 360–366 (2006). https://doi.org/10.1111/j.1745-7254.2006.00291.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2006.00291.x
Keywords
This article is cited by
-
Computational analyses of curcuminoid analogs against kinase domain of HER2
BMC Bioinformatics (2014)
-
Pure curcumin decreases the expression of WT1 by upregulation of miR-15a and miR-16-1 in leukemic cells
Journal of Experimental & Clinical Cancer Research (2012)
-
Effect of pure curcumin, demethoxycurcumin, and bisdemethoxycurcumin on WT1 gene expression in leukemic cell lines
Cancer Chemotherapy and Pharmacology (2008)
-
Inhibitory effect of curcumin onMDR1 gene expression in patient leukemic cells
Archives of Pharmacal Research (2006)