Advertisement

Archives of Pharmacal Research

, Volume 28, Issue 1, pp 68–72 | Cite as

Pseudolaric acid B induces apoptosis through p53 and bax/ Bcl-2 pathways in human melanoma a375-s2 cells

  • Xian-Feng Gong
  • Min-Wei Wang
  • Shin-Ichi Tashiro
  • Satoshi Onodera
  • Takashi IkejimaEmail author
Article Drug development

Abstract

Pseudolaric acid B is a major compound found in the bark ofPseudolarix kaempferi Gordon. In our study, pseudolaric acid B inhibited growth of human melanoma cells, A375-S2 in a time-and dose-dependent manner. A375-S2 cells treated with pseudolaric acid B showed typical characteristics of apoptosis including morphologic changes, DNA fragmentation, sub-diploid peak in flow cytometry, cleavage of poly-ADP ribose polymerase (PARP) and degradation of inhibitor of caspase-activated DNase (ICAD). P53 protein expression was upregulated while cells were arrested at the G2/M phase of the cell cycle. There was a decrease in the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins, whereas pro-apoptotic Bax was increased. The two classical caspase substrates, PARP and ICAD, were both decreased in a time-dependent manner, indicating the activation of downstream caspases.

Key words

Pseudolaric acid B Apoptosis A375-S2 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Agarwal, N. and Mehta, K., Possible involvement of Bcl-2 pathway in retinoid X receptor alpha-induced apoptosis of HL-60 cells.Biochem. Biophys. Res. Comm., 230, 251–253 (1997).PubMedCrossRefGoogle Scholar
  2. Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., and Nagata, S., A., Caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD.Nature, 391, 43–50 (1998).PubMedCrossRefGoogle Scholar
  3. Hermeking, H., Lengauer, C., Polyak, K., He, T. C., Zhang, L., Thiagalingam, S., Kinzler, K. W., and Vogelstein, B., 14-3-3-Sigma is a p53-regulated inhibitor of G2/M progression.Mol. Cell, 1, 3–11 (1997).PubMedCrossRefGoogle Scholar
  4. Hockenbery, D. M., Oltvai, Z. N., Yin, X. M., Milliman, C. L., and Korsmeyer, S. J., Bcl-2 functions in an antioxidant pathway to prevent apoptosis.Cell, 75, 241–251 (1993).PubMedCrossRefGoogle Scholar
  5. Kastan, M.B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R.W., Participation of p53 protein in cellular response to DNA damage.Cancer Res., 51, 6304–6311 (1991).PubMedGoogle Scholar
  6. Kerr, J.F., Wyllie, A.H., and Currie, A.R., Apoptosis: a basic biologic phenomenon with wide-ranging implications in tissue kinetics.Br. J. Cancer, 26, 239–257 (1972).PubMedGoogle Scholar
  7. Lane, D.P., p53, guardian of the genome.Nature, 258, 15–16 (1992).CrossRefGoogle Scholar
  8. Lazebnik, Y. A., Kaufmann, S. H., Desnoyers, S., Poirier, G. G., and Earnshaw, W. C., Cleavage of poly (ADP-ribose) polymerase by a proteinase with properties like ICE.Nature, 371, 346–347 (1994).PubMedCrossRefGoogle Scholar
  9. Li, E., Clark, A. M., and Hufford, C. D., Antifungal evaluation of pseudolaric acid B, a major constituent ofpseudolarix kaempferi.J. Nat. Prod., 58, 57–67 (1995).PubMedCrossRefGoogle Scholar
  10. Liu, X. S., Zou, H., Slaughter, C., and Wang, X., DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis.Cell, 89, 175–184 (1997).PubMedCrossRefGoogle Scholar
  11. Mengubas, K., Riordan, F. A., Hoffbrand, V., and Wickremasinghe, G., Co-ordinated downregulation of Bcl-2 and Bax expression during granulocytic and macrophage-like differentiation of the HL60 premyelocytic leukemia cell line.FEBS. Lett., 394, 356–360 (1996).PubMedCrossRefGoogle Scholar
  12. Nicholson, D. W., Ali, A., Thomberry, N. A., Vaillancourt, J. P., Ding, C. K., Gallant, M., Gareau, Y., Griffin, P. R., Labelle, M., and Lazebnik, Y. A., Identification and inhibition of the ICE/ CED-3 protease necessary for mammalian apoptosis.Nature, 376, 37–43 (1995).PubMedCrossRefGoogle Scholar
  13. Pan, D. J., Li, Z. L., Hu, C. Q., Chen, K., Chang, J. J., and Lee, K. H., The cytotoxic principles ofPseudolarix Kaempferi: Pseudolaric acid-A and B and related derivatives.Planta Med., 56, 383–385 (1990).PubMedCrossRefGoogle Scholar
  14. Sakahira, H., Enari, M., and Nagata, S., Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis.Nature, 391, 96–99 (1998).PubMedCrossRefGoogle Scholar
  15. Schwartz, D., Almong, N., Peled, A., Goldfinger, N., and Rotter, V., Role of wild-type p53 in the G2 phase: regulation of the α-irradiation induced delay and DNA repair.Oncogene, 15, 2597–2607 (1997).PubMedCrossRefGoogle Scholar
  16. Stewart, N., Hicks, G. G., Paraskevans, F., and Mowat, M., Evidence for a second cell cycle block at G2/M by p53.Oncogene, 10, 109–115 (1995).PubMedGoogle Scholar
  17. Taylor, W.R., and Stark, G.R., Regulation of the G2/M transition by p53.Oncogene, 20, 1803–1815 (2001).PubMedCrossRefGoogle Scholar
  18. Wang, W. C., Lu, R.F., Zhao, S. X., and Gu, Z. P., Comparison of early pregnancy-terminating effect and toxicity between pseudolaric acids A and B.Acta. Pharmacol. Sin., 9, 445–448 (1988).Google Scholar
  19. Wang, W. C., Lu, R. F., Zhao, S. X., and Zhu, Y. Z., Antifertility effect of pseudolaric acid B.Acta. Pharmacol. Sin., 3, 188–192 (1982).Google Scholar
  20. Wu, L. X., Xu, J. H., Wu, G. H., and Chen, Y. Z., Inhibitory effect of curcumin on proliferation of K562 cells involves down-regulation of p210bcr/abl-initiated Ras signal transduction pathway.Acta. Pharmacol. Sin., 11, 1155–1160 (2003).Google Scholar
  21. Yue, T. L., Ohlstein, H. E., and Ruffolo, R. R., Apoptosis: a potential target for discovering novel therapies for cardiovascular diseases.Curr. Opin. Chem. Biol., 3, 474–480 (1999).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2005

Authors and Affiliations

  • Xian-Feng Gong
    • 1
    • 2
  • Min-Wei Wang
    • 2
  • Shin-Ichi Tashiro
    • 3
  • Satoshi Onodera
    • 3
  • Takashi Ikejima
    • 1
    Email author
  1. 1.China-Japan Research Institute of Medical and Pharmaceutical SciencesShenyangChina
  2. 2.Department of PharmacologyShenyang Pharmaceutical UniversityShenyangChina
  3. 3.Department of Clinical and Biomedical SciencesShowa Pharmaceutical UniversityTokyoJapan

Personalised recommendations