DOI QR코드

DOI QR Code

Curcumin Induces Apoptosis and Inhibits Growth of Human Burkitt's Lymphoma in Xenograft Mouse Model

  • Li, Zai-xin (College of Bioengineering, Chongqing University) ;
  • Ouyang, Ke-qing (College of Bioengineering, Chongqing University) ;
  • Jiang, Xv (Key Laboratory of Brain Functional Genomics, Ministry of Education and Science and Technology Commission of Shanghai Municipality, East China Normal University) ;
  • Wang, Dong (Key Laboratory of Brain Functional Genomics, Ministry of Education and Science and Technology Commission of Shanghai Municipality, East China Normal University) ;
  • Hu, Yinghe (Key Laboratory of Brain Functional Genomics, Ministry of Education and Science and Technology Commission of Shanghai Municipality, East China Normal University)
  • Received : 2008.03.27
  • Accepted : 2008.12.19
  • Published : 2009.03.31

Abstract

Curcumin, a natural compound extracted from rhizomes of curcuma Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor and anti-oxidative properties. However, the mechanism of action of the compound remains poorly understood. In this report, we have analyzed the effects of curcumin on the cell proliferation of Burkitt's lymphoma Raji cells. The results demonstrated that curcumin could effectively inhibit the growth of Raji cells in a dose- and time-dependent manner. Further studies indicated that curcumin treatment resulted in apoptosis of cells. Biochemical analysis showed that the expression of Bax, Bid and cytochrome C were up-regulated, while the expression of oncogene c-Myc was down regulated after curcumin treatment. Furthermore, poly (ADP-ribose) polymerase (PARP) cleavage was induced by the compound. Interestingly, the antiapoptotic Bcl-2 expression was not significantly changed in Raji cells after curcumin treatment. These results suggested that the mechanism of action of curcumin was to induce mitochondrial damage and therefore led to Raji cell apoptosis. We further investigated the in vivo effects of curcumin on the growth of xenograft tumors in nude mice. The results showed that curcumin could effectively inhibit tumor growth in the xenograft mouse model. The overall results showed that curcumin could suppress the growth of Burkitt's lymphoma cells in both in vitro and in vivo systems.

Keywords

Acknowledgement

Supported by : Ministry of Science and Technology of China, Shanghai Commission for Science and Technology, Shanghai Commission for Education

References

  1. Adachi, S., Obaya, A.J., Han, Z., Desimone, N.R., Wyche, J.H., and Sedivy, J.M. (2001). c-Myc is necessary for DNA damageinduced apoptosis in the G2 phase of the cell cycle. Mol. Cell. Biol. 21, 4929-4937 https://doi.org/10.1128/MCB.21.15.4929-4937.2001
  2. Aggarwal, B.B, Kuma, R.A., and Bharti, A.C. (2003). Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 23, 363-398
  3. Akasaka, T., Akasaka, H., Ueda, C., Yonetani, N., Maesako, Y., Shimizu, A., Yamabe, H., Fukuhara, S., Uchiyama, T., and Ohno, H. (2000). Molecular and clinical features of non-Burkitt's, diffuse large-cell lymphoma of B-Cell type associated with the c-Myc/Immunoglobulin heavy-chain fusion gene. J. Clin. Oncol. 18, 510 https://doi.org/10.1200/JCO.2000.18.3.510
  4. Anke, M.J., Eekelen, V., Shammas, F.V., Wee, L., Heikkil, A.R., and Osland, A. (2000). Quantitative analysis of cytokeratin 20 Gene expression using RT-PCR and capillary electrophoresis with fluorescent DNA detection. Clin. Biochem. 33, 457-464 https://doi.org/10.1016/S0009-9120(00)00155-7
  5. Anto, R.J., Mukhopadyay, A., Denning, K., and Aggarwal, B.B. (2002). Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, Bid cleavage and cytochrome C release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 23, 143-150 https://doi.org/10.1093/carcin/23.1.143
  6. Balasubramanyam, K., Varier, R.A., Altaf, M., Swaminathan, V., Siddappa, N.B., Ranga, U., and Kundu, T.K. (2004). Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription J. Biol. Chem. 279, 51163-51171 https://doi.org/10.1074/jbc.M409024200
  7. Beato, M.S., Aguilera, A.S., and Piris, M.A. (2003). Cell cycle deregulation in B-cell lymphomas. Blood 101, 1220-1235 https://doi.org/10.1182/blood-2002-07-2009
  8. Boulares, A.H., Yakovlev, A.G., Ivanova,V., Stoica, B.A., Wang, G., Iyer, S., and Smulson, M. (1999). Role of poly (ADP-ribose) polymerase (PARP) cleavage in apoptosis. J. Biol. Chem. 274, 22932-22940 https://doi.org/10.1074/jbc.274.33.22932
  9. Boulares, A.H., Yakovlev, A.G., Ivanova, V., Stoica, B.A., Wang, G., Iyer, S., and Smulson, M. (2007). Resveratrol inhibits IL-1 $\beta$-induced stimulation of caspase-3 and cleavage of PARP in human articular chondrocytes in vitro. Ann. NY. Acad. Sci. 1095, 554-563 https://doi.org/10.1196/annals.1397.060
  10. Bowman, W.P., Shuster, J.J., Cook, B., Griffin, T., Behm, F., Pullen, J., Link, M., Head, D., Carroll, A., Berard, C., et al. (1996). Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a Pediatric Oncology Group study. J. Clin. Oncol. 14, 1252-1261 https://doi.org/10.1200/JCO.1996.14.4.1252
  11. Budhia, S., Haring, L.F., Connell, I., and Blacklaws, B.A. (2006). Quantitation of ovine cytokine mRNA by real-time RT–PCR. J. Immunol. Meth. 309, 160-172 https://doi.org/10.1016/j.jim.2005.12.006
  12. Cairo, M.S., Sposto, R., Perkins, S.L., Meadows, A.T., Hoover-Regan, M.L., Anderson, J.R., Siegel, S.E., Lones, M.A., Tedeschi-Blok, N., and Kadin, M.E. (2003). Burkitt's and Burkittlike lymphoma in children and adolescents: a review of the children's cancer group experience. Br. J. Haematol. 120, 660-670 https://doi.org/10.1046/j.1365-2141.2003.04134.x
  13. Cao, J., Liu, Y., Li, J., Zhou, H.M., Kong, Y., Yang. G., Jiang, L.P., Li, Q.J., and Zhong, L.F. (2007). Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma $G_2$ cells. Free Radic. Biol. Med. 13, 1-8 https://doi.org/10.1016/0891-5849(92)90158-D
  14. Chen, Z., and Zhu, S. (2007). An optimized in vitro assay for screening compounds that stimulate liver cell glucose utilization with low cytotoxicity. J. Pharmacol. Toxicol. 56, 58-62 https://doi.org/10.1016/j.vascn.2006.12.005
  15. Cregan, S.P., Fortin, A., Maclaurin, J.G., Callaghan, S.M., Cecconi, F., Woon, S.Y., Dawson, T.M., Dawson, V.L., Park, D.S., Kroemer, G., et al. (2002). Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J. Cell Biol. 158, 507-517 https://doi.org/10.1083/jcb.200202130
  16. Cutrona, G., Carpaneto, E.M., Ponzanelli, A., Ulivi, M., Millo, E., Scarfì, S., Roncella, S., Benatti, U., Boffa, L.C., and Ferrarini, M.(2003). Inhibition of the translocated c-Myc in Burkitt's lymphoma by a PNA complementary to the E$\mu$ enhancer. Cancer Res. 63, 6144-6148
  17. Delettre, C., Yuste, V.J., Moubarak, R.S., Bras, M., Robert, N., and Susin, S.A. (2006). Identification and characterization of AIFsh2, a mitochondrial apoptosis-inducing factor (AIF) isoform with NADH oxidase activity. J. Biol. Chem. 281, 18507-18518 https://doi.org/10.1074/jbc.M601751200
  18. Evan, G.I., Wyllie, A.H., Gilbert, C.S., Littlewood, T.D., Land, H., Brooks, M., Waters, C.M., Penn, L.Z., and Hancock, D.C.(1992). Induction of apoptosis in fibroblasts by c-Myc protein. Cell 69, 119-128 https://doi.org/10.1016/0092-8674(92)90123-T
  19. Fabre, I., Fabre, G., Lena, N., and Cano, J.P. (1986). Kinetics of uptake and intracellular binding of cyclosporine an in Raji cells in vitro.. Biochem. Pharmacol. 35, 4261-4266 https://doi.org/10.1016/0006-2952(86)90704-5
  20. Fang, J., Lu, J., and Holmgren, A. (2005). Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. J. Biol. Chem. 280, 25284-25290 https://doi.org/10.1074/jbc.M414645200
  21. Ferry, J.A. (2006). Burkitt's lymphoma:clinicopathologic features and differential diagnosis. Oncologist 11, 375-383 https://doi.org/10.1634/theoncologist.11-4-375
  22. Gajate, C., Feiyun, A., and Mollinedo, F. (2003). Rapid and selective apoptosis in human leukemic cells induced by aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. Clin. Cancer Res. 9, 1535-1545
  23. Han, S.S., Chung, S.T., Robertson, D.A., Ranjan, D., and Bondada, S. (1999). Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-Myc, bcl-$X_L$, NF-$\kappa$B, p53. Clin. Immunol. 93, 152-161 https://doi.org/10.1006/clim.1999.4769
  24. Hussain, A.R., Rasheed, M., Manogaran, P.S., Kuraya, K.S., and Uddin, S. (2005). Complete loss or severely compromised expression of the pro-apoptotic protein Bax leads to resistance to curcumin-induced apoptosis in Burkitt's lymphoma cells. Blood 106, 1928-1938
  25. Juin, P., Hunt, A., Littlewood, T., Griffiths, B., Swigart, L.B., Korsmeyer, S., and Evan, G. (2002). c-Myc functionally cooperates with Bax to induce apoptosis. Mol. Cell. Biol. 22, 6158-6169 https://doi.org/10.1128/MCB.22.17.6158-6169.2002
  26. Jung, E.M., Lim, J.H., Lee, T.J., Park, J., Choi, K.S., and Kwon, T.K.(2005). Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5(DR5). Carcinogenesis 26, 1905-1913 https://doi.org/10.1093/carcin/bgi167
  27. Kanda, K., Wong, W., and Boxer, L.M. (2004). Enhanced apoptosis to chemotherapeutic agents is dependent on NF-$\kappa$B and Bcl-2-related proteins but is independent of p53 and Bax in Burkitt's Lymphoma cells. Blood 104, 1541
  28. Kelly, G. L., Stylianou, J., Bell, A. I., We, W. I., Rowe, M., and Rickinson, A.B. (2007). Three restricted forms of epstein-Barr virus latency counteracting apoptosis in c-Myc expressing Burkitt lymphoma cells. Blood 110, 1572
  29. Kroemer, G., and Reed, J.C. (2000). Mitochondrial control of cell death. Nat. Med. 6, 513-519 https://doi.org/10.1038/74994
  30. Kunnumakkara, A.B., Guha, S., Krishnan, S., Diagaradjane, P., Gelovani, J., and Aggarwal, B.B. (2007). Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-$\kappa$$\beta$-regulated gene products. Cancer Res. 67, 3853-3861 https://doi.org/10.1158/0008-5472.CAN-06-4257
  31. Lee, D., Kim, S., Ko, O.B., Koo, J.E., Chong, Y.P., Huh, J., and Suh, C. (2005). Burkitt's lymphoma in Korea: clinical manifestations and efficacy of modified CALGB 9251 regimen (BNHL). Blood 106, 4661-4673
  32. Li, J.E., Wu, W.L., and Wang, Z.Y. (2002). Apoptotic effect of $As_2S_2$ on K562 cells and its mechanism. Acta Pharmacol. Sin. 23, 991-996
  33. Liu, P.L., Chen, Y.L., Chen, Y.H., Lin, S.J., and Kou, Y.R. (2005). Wood smoke extract induces oxidative stress-mediated caspase-independent apoptosis in human lung endothelial cells:role of AIF and EndoG. Am. J. Physiol. Lung Cell Mol. Physiol. 289, 739-749 https://doi.org/10.1152/ajplung.00099.2005
  34. Martin K.R. (2006). Targeting apoptosis with dietary bioactive agents. Exp. Biol. Med. 231, 117-129 https://doi.org/10.1177/153537020623100201
  35. Mitchell, K.O., Ricci, M.S., Miyashita, T., Dicker, D.T., Jin, Z., Reed, J.C., and El-Deiry, W.S. (2000). Bax is a transcriptional target and mediator of c-Myc-induced apoptosis. Cancer Res. 60, 6318-6325
  36. Moos, P.J., Edes, K., Mullally, J.E., and Fitzpatrick, F.A. (2004). Curcumin impairs tumor suppressor p53 function in colon cancer cells. Carcinogenesis 25, 1611-1617 https://doi.org/10.1093/carcin/bgh163
  37. Morin, D., Barhelemy, S., Zini, R., Labidalle, S., and Tillement, J.P.(2001). Curcumin induces the mitochondrial permeability transition pore mediated by membrane protein thiol oxidation. FEBS Lett. 495, 131-136 https://doi.org/10.1016/S0014-5793(01)02376-6
  38. Nieminen, A.I., Partanen, J.I., Hau, A., and Klefstrom, J. (2007). c-Myc primed mitochondria determine cellular sensitivity to TRAILinduced apoptosis. EMBO J. 26, 1055-1067 https://doi.org/10.1038/sj.emboj.7601551
  39. Odot, J., Albert, P., Carlier, A., Tarpin, M., Devy, J., and Madoulet, C. (2004). in vitro and in vivo anti-tumoral effect of curcumin against melanoma cells. Int. J. Cancer 111, 381-387 https://doi.org/10.1002/ijc.20160
  40. Park, J.K., Min, C.Y., Seongman, K., Jaeuk, K., Taik, K., Kim, H.J., Kim, Y.H., Kim, J.S., and Young, D.Y. (2002). c-Myc exerts a protective function through ornithine decarboxylase against cellular insults. Mol. Pharmacol. 62, 1400-1408 https://doi.org/10.1124/mol.62.6.1400
  41. Pelengaris, S., Khan, M., and Evan, G. (2002). c-Myc: more than just a matter of life and death. Nature 2, 764-777 https://doi.org/10.1038/nrc904
  42. Rao, C.V., Rivenson, A., Simi, B., and Reddy, B.S. (1995). Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res. 55, 259-266
  43. Rashmi, R., Kumar, S., and Karunagaran, D. (2004). Ectopic expression of Bcl-XL or Ku70 protects human colon cancer cells (SW480) against curcumin-induced apoptosis while their downregulation potentiates it. Carcinogenesis 25, 1867-1877 https://doi.org/10.1093/carcin/bgh213
  44. Salvioli, S., Sikora, E., Cooper, E.L., and Franceschi, C. (2007). Curcumin in cell death processes: A challenge for CAM of agerelated pathologies. Evid. Based Complement. Alternat. Med. 4, 181-190 https://doi.org/10.1093/ecam/nem043
  45. Schimmer, A.D., Hedley, D.W., Penn, L.Z., and Minden, M.D.(2001). Receptor- and mitochondrial- mediated apoptosis in acute leukemia: a translational view. Blood 98, 3541-3553 https://doi.org/10.1182/blood.V98.13.3541
  46. Shankar, S., and Srivastava, R.K. (2007). Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric. Carcinogenesis 28, 1277-1286 https://doi.org/10.1093/carcin/bgm024
  47. Sharma, R.A., Ireson, C.R., Verschoyle, R.D., Hill, K.A., Williams, M.L., Leuratti, C., Manson, M.M., Marnett, L.J., Steward, W.P., and Gescher, A. (2001). Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. Clin. Cancer Res. 7, 1452-1459
  48. Simeonova, E., Garstka, M., Koziol-Lipinska, J., and Mostowska, A. (2004). Monitoring the mitochondrial transmembrane potential with the JC-1 fluorochrome in programmed cell death during mesophyll leaf senescence. Protoplasma 223, 143-153 https://doi.org/10.1007/s00709-004-0039-5
  49. Siu, P.M., and Always, S.E. (2005). Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle. J. Physiol. 565, 309-323 https://doi.org/10.1113/jphysiol.2004.081083
  50. Somasundaram, S., Edmund, N.A., Moore, D.T., Small, G.W., Shi, Y.Y., and Orlowski, R.Z. (2002). Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res. 62, 3868-3875
  51. Sun, S.Y., Hai, N., and Lotan, R.J. (2004). Apoptosis as a novel target for cancer chemoprevention. J. Nat. Cancer Inst. 96, 662-672 https://doi.org/10.1093/jnci/djh123
  52. Susin, S.A., Lorenzo, H.K., and Zamzami, N. (1999). Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441-446 https://doi.org/10.1038/17135
  53. Syng-Ai, C., Kumari, A.L., and Khar, A. (2004). Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2. Mol. Cancer Ther. 3,1101-1108
  54. Trenfield, K., and Masters, C.J. (1978). On the variation in enzyme activities during the growth of burkitts lymphoma cells in suspension culture. Int. J. Biochem. 9, 823-828 https://doi.org/10.1016/0020-711X(78)90031-9
  55. Voog, B.E., Bienvenu, J., Warzocha, K., Moullet, I., Dumontet, C., Thieblemont, C., Monneret, G., Gutowski, M.C., Coiffier, B., and Salles, G. (2000). Factors that predict chemotherapy-induced myelosuppression in lymphoma patients: role of the tumor necrosis factor ligand-receptor system. J. Clin. Oncol. 18, 325-331 https://doi.org/10.1200/JCO.2000.18.2.325
  56. Wang, X.C., Yang, C.L., Chai, J.J., Shi, Y.G., and Ding, X. (2002). Mechanisms of AIF-mediated apoptotic DNA degradation in caenorhabditis elegans. Science 298, 1587-1591 https://doi.org/10.1126/science.1076194
  57. Yi, X.L., Yin, X.M., and Dong, Z. (2003). Inhibition of Bid-induced apoptosis by Bcl-2, tBid insertion, Bax translocation and Bax/Bak oligomerization suppressed. J. Biol. Chem. 278, 16992-16999 https://doi.org/10.1074/jbc.M300039200
  58. Zirong, L., Calcar, S.V., Chunxu, Q., Cavenee, W.K., Michael, Q.Z., and Bing, R. (2003). A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells. Proc. Natl. Acad. Sci. USA 100, 8164-8169 https://doi.org/10.1073/pnas.1332764100

Cited by

  1. The heat shock protein 27 (Hsp27) operates predominantly by blocking the mitochondrial-independent/extrinsic pathway of cellular apoptosis vol.27, pp.5, 2009, https://doi.org/10.1007/s10059-009-0079-y
  2. Turmeric : An Overview of Potential Health Benefits vol.45, pp.5, 2009, https://doi.org/10.1097/nt.0b013e3181f1d72c
  3. In vitroeffects of plant and mushroom extracts on immunological function of chicken lymphocytes and macrophages vol.51, pp.2, 2009, https://doi.org/10.1080/00071661003745844
  4. A natural compound, methyl angolensate, induces mitochondrial pathway of apoptosis in Daudi cells vol.29, pp.4, 2009, https://doi.org/10.1007/s10637-010-9393-7
  5. Curcumin Induces Apoptosis in EJ Bladder Cancer Cells via Modulating C-Myc and PI3K/Akt Signaling Pathway vol.2, pp.3, 2009, https://doi.org/10.4021/wjon335w
  6. A novel anti-lymphoma protein RE26 from Rozites emodensis (Berk.) Moser vol.93, pp.3, 2009, https://doi.org/10.1007/s00253-011-3450-9
  7. Curcumin improves the antitumor effect of X-ray irradiation by blocking the NF-&kgr;B pathway: an in-vitro study of lymphoma vol.23, pp.6, 2009, https://doi.org/10.1097/cad.0b013e3283503fbc
  8. Curcuma Contra Cancer? Curcumin and Hodgkin’s Lymphoma vol.6, pp.None, 2009, https://doi.org/10.4137/cgm.s11113
  9. Curcumin in various cancers vol.39, pp.1, 2013, https://doi.org/10.1002/biof.1068
  10. CELLFOOD™ induces apoptosis in human mesothelioma and colorectal cancer cells by modulating p53, c-myc and pAkt signaling pathways vol.33, pp.1, 2014, https://doi.org/10.1186/1756-9966-33-24
  11. The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer vol.66, pp.1, 2014, https://doi.org/10.1124/pr.110.004044
  12. Synthesis of novel coumarin nucleus-based DPA drug-like molecular entity: In vitro DNA/Cu(II) binding, DNA cleavage and pro-oxidant mechanism for anticancer action vol.12, pp.8, 2017, https://doi.org/10.1371/journal.pone.0181783
  13. Curcumin inhibits liver metastasis of gastric cancer through reducing circulating tumor cells vol.11, pp.5, 2009, https://doi.org/10.18632/aging.101848
  14. Curcumin and Cancer vol.11, pp.10, 2019, https://doi.org/10.3390/nu11102376
  15. MiR-28-5p mediates the anti-proliferative and pro-apoptotic effects of curcumin on human diffuse large B-cell lymphoma cells vol.48, pp.7, 2009, https://doi.org/10.1177/0300060520943792
  16. Curcumin sensitizes Epstein‑Barr‑immortalized lymphoblastoid cell lines to inorganic arsenic toxicity vol.22, pp.2, 2021, https://doi.org/10.3892/etm.2021.10304