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The Pharmaceutical Society of Korea (대한약학회)
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The Antitumor Effects of Selenium Compound $Na_5SeV_5O_{18}{\cdot}3H_2O$ in K562 Cell

  • Yang, Jun-Ying (School of Life Sciences, Lanzhou University,Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, College of Pharmacy, Lanzhou University) ;
  • Wang, Zi-Ren (School of Life Sciences, Lanzhou University)
  • Published : 2006.10.01
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Abstract

With an approach to study the anti-tumor effects and mechanism of selenium compound, we investigated the anti-tumor activity and mechanism of $Na_5SeV_5O_{18}{\cdot}3H_2O$ (NaSeVO) in K562 cells. The results showed that $0.625{\sim}20\;mg/L$ NaSeVO could significantly inhibit the proliferation of K562 cells in vitro in a time- and concentration-dependent manner as determined by microculture tetrazolium (MTT) assay, the IC50 values were 14.41 (4.45-46.60) and 3.45 (2.29-5.22) mg/L after 48 hand 72 h treatment with NaSeVO respectively. In vivo experiments demonstrated that i.p. administration of 5, 10 mg/kg NaSeVO exhibited an significant inhibitory effect on the growth of transplantation tumor sarcoma 180 (S180) and hepatoma 22 (H22) in mice, with inhibition rate 26.8% and 58.4% on S180 and 31.3% and 47.4% on H22, respectively. Cell cycle studies indicated that the proportion of G0/G1 phase was increased at 2.5 mg/L while decreased at 10 mg/L after treatment for 24, 48 h. Whereas S phase was decreased at 2.5-5 mg/L and markedly increased at 10 mg/L after treatment for 48 h. After treatment for 24 h, 10 mg/L NaSeVO also markedly increased S and G2/M phases. Take together, the result clearly showed that NaSeVO markedly increased S and G2/M phases at 10 mg/L. The study of immunocytochemistry showed that the expression bcl-2 is significantly inhibited by 10 mg/L NaSeVO, and bax increased. Morphology observation also revealed typical apoptotic features. NaSeVO also significantly caused the accumulation of $Ca^{2+}$ and $Mg^{2+}$, reactive oxygen species (ROS) and the reduction of pH value and mitochondrial membrane potential in K562 cells as compared with control by confocal laser scanning microscope. These results suggest that NaSeVO has anti-tumor effects and its mechanism is attributed partially to apoptosis induced by the elevation of intracellular $Ca^{2+}$, $Mg^{2+}$ and ROS concentration, and a reduction of pH value and mitochondria membrane potential (MMP).

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References

  1. Benner, E., Bishop, M. R., Agarwal, N., Iversen, P., and Joshi, S. S., Combination of antisense oligonucleotide and low-dose chemotherapy in hematological malignancies. Pharmacol. Toxicol. Methods., 37, 229-235 (1997) https://doi.org/10.1016/S1056-8719(97)00034-8
  2. Bolduc, J. S., Denizeau, F., and Jumarie, C., Cadmium-induced mitochondrial membrane-potential dissipation does not necessarily require cytosolic oxidative stress: studies using rhodamine-123 fluorescence unquenching. Toxicol. Sci., 77, 299-306 (2004) https://doi.org/10.1093/toxsci/kfh015
  3. Burney, P. G., Comstock, G. W., and Morris, J. S., Pancreatic cancer. Clin. Nutr., 49, 895-900 (1997)
  4. Cain, K., Inayat-Hussain, S. H., Kokileva, L., and Cohen, G. M., DNA cleavage in rat liver nuclei activated by $Mg^{2+}$ or $Ca^{2+}$ +$Mg^{2+}$ is inhibited by a variety of structurally unrelated inhibitors. Biochem. Cell Biol., 72, 631-638 (1994) https://doi.org/10.1139/o94-083
  5. Cotter, T. G. and Fernanded, R. S., Activation of a calcium magnesium independent endonuclease in human leukemic cell apoptosis. Anticancer Res., 13, 1253-1259 (1993)
  6. El-Bayoumy, K., The protective role of selenium on genetic damage and cancer. Mutat. Res., 475, 123-139 (2001) https://doi.org/10.1016/S0027-5107(01)00075-6
  7. Foster, L. H. and Sumar, S., Selenium in health and disease: a review. Crit. Rev. Food Sci. Nutr., 37, 211-28 (1997) https://doi.org/10.1080/10408399709527773
  8. Gasparian, A. V., Yao, Y. J., Lu, J., Yemelyanov, A. Y., Lyakh, L. A., Slaga, T. J., and Budunova, I. V., Selenium compounds inhibit I$\kappa$B Kinase (IKK) and Nuclear Factor-$\kappa$B (NF-$\kappa$B) in prostate cancer cells. Mol. Cancer Ther., 1, 1079-1087 (2002)
  9. Glattre, E., Thomassen, Y., Haldorsen, T., Lund-Larsen, P. G., Theodorsen, L., and Aaseth, J., Prediagnostic serum selenium in a case-control study of thyroid cancer. Int. Epidemiol., 18, 45-49 (1989) https://doi.org/10.1093/ije/18.1.45
  10. Huang, Y. L., Sheu, J. Y., and Lin, T. H., Association between oxidative stress and changes of trace elements in patients with breast cancer. Clin. Biochem., 32, 131-136 (1999) https://doi.org/10.1016/S0009-9120(98)00096-4
  11. Ip, C., Lessons from basic research in selenium and cancer prevention. Nutr., 128, 1845-1854 (1998) https://doi.org/10.1093/jn/128.11.1845
  12. Ip, C., Dong, Y., and Ganther, H. E., New concepts in selenium chemoprevention. Cancer Met. Rev., 21, 281- 289 (2002) https://doi.org/10.1023/A:1021263027659
  13. Jacobson, M. D., Reactive oxygen species and programmed cell death. Trends Biochem. Sci., 21, 83-86 (1996) https://doi.org/10.1016/S0968-0004(96)20008-8
  14. Jaskiewicz, K., Marasas, W. F., Rossouw, J. E., Van Niekerk, F. E., and Heine Tech, E. W. P., Selenium and other mineral elements in populations at risk for esophageal cancer. Cancer, 62, 2635-2639 (1988) https://doi.org/10.1002/1097-0142(19881215)62:12<2635::AID-CNCR2820621232>3.0.CO;2-5
  15. Jung, U., Zheng, X.-X., Yoon, S.-O., and Chung, A.-S., Se- Methylselenocysteine induces apoptosis mediated by reactive oxygen species in HL-60 cells. Free Radic. Biology & Med., 31, 479-489 (2001)
  16. Kamesaki, H., Mechanisms involved in chemotherapy-induced apoptosis and their implications in cancer chemotherapy. Int. Hematol., 68, 29-43 (1998) https://doi.org/10.1016/S0925-5710(98)00038-3
  17. Kornblau, S. M., The role of apoptosis in the pathogenesis, prognosis, and therapy of hematologic malignancies. Leukemia, 12, 41-46 (1998)
  18. Lowe, S. W. and Lin, A. W., Apoptosis in cancer. Carcinogenesis, 21, 485-495 (2000) https://doi.org/10.1093/carcin/21.3.485
  19. McConkey, D. J., and Orrenius, S., The role of calcium in the regulation of apoptosis. Leukocyte. Biol., 59, 775-783 (1996) https://doi.org/10.1002/jlb.59.6.775
  20. Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Immunol. Methods., 65, 55-63 (1983) https://doi.org/10.1016/0022-1759(83)90303-4
  21. Munaron, L., Antoniotti, S., Pla, A. F., and Lovisolo, D., Blocking $Ca^{2+}$ entry: a way to control cell proliferation. Curr. Med. Chem., 12, 1533-1543 (2004)
  22. Nicholls, D. G., and Ward, M. W., Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts. Trends Neurosci., 23, 166-174 (2000) https://doi.org/10.1016/S0166-2236(99)01534-9
  23. Philipov, P. and Tzatchev, K., Selenium concentrations in serum of patients with cerebral and extracerebral tumors. Zentralbl. Neurochir., 49, 344-347 (1988)
  24. Rojas, E., Herrera, L. A., Poirier, L. A., and Ostrosky-Wegman, P., Are metals dietary carcinogens? Mutat. Res., 443, 157- 181 (1999) https://doi.org/10.1016/S1383-5742(99)00018-6
  25. Shamberger, R. J., The genotoxicity of selenium. Mutat. Res., 154, 29-48 (1985) https://doi.org/10.1016/0165-1110(85)90008-9
  26. Shilo, S., Aronis, A., Komarnitsky, R., and Tirosh, O., Selenite sensitizes mitochondrial permeability transition pore opening in vitro and in vivo: a possible mechanism for chemoprotection. Biochem., 370, 283-290 (2003) https://doi.org/10.1042/BJ20021022
  27. Simon, S. M., Roy, D., and Schindler, M., Intracellular pH and the control of multidrug resistance. Proc. Natl. Acad. Sci., 91, 1128-1132 (1994)
  28. Sinha, R., and El-Bayoumy, K., Apoptosis is a critical cellular event in cancer chemoprevention and chemotherapy by selenium compounds. Curr. Cancer Drug Targets, 4, 13-28 (2004) https://doi.org/10.2174/1568009043481614
  29. Sinha, R., Bansal, M. P., Ganther, H., and Medina, D., Significance of selenium-labeled proteins for selenium's chemopreventive functions. Carcinogenesis, 14, 1895-1900 (1993) https://doi.org/10.1093/carcin/14.9.1895
  30. Wand, W. R., In vivo methods. In Teicher, B.A. (Ed). Anticancer drug development guide, preclinical screening, clinical trials, and approval. Humana Press Inc., Totowa, NJ, pp. 59-213, (1997)
  31. Wang H. T., Yang X. L., Zhang Z. H., Lu J. L., and Xu H. B., Reactive oxygen species from mitochondria mediate SW480 cells apoptosis induced by $Na_2SeO_3$. Biol. Trace Elem. Res., 85, 241-54 (2002) https://doi.org/10.1385/BTER:85:3:241
  32. Wang, X. W., Role of p53 and apoptosis in carcinogenesis. Anticancer Res., 19, 4759-4771 (1999)
  33. Westin, T., Ahlbom, E., Johansson, E., Sandstrom, B., Karlberg, I., and Edstrom, S., Circulating levels of selenium and zinc in relation to nutritional status in patients with head and neck cancer. Arch. Otolaryngol. Head Neck Surg., 115, 1079-1082 (1989) https://doi.org/10.1001/archotol.1989.01860330069019
  34. Zhong, W. and Oberley, T. D., Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line. Cancer Res., 61, 7071-7078 (2001)