Skip to main content

Cartilage polysaccharide induces apoptosis in human leukemia K562 cells

Cell Biology and Toxicology volume 23, pages 465–476 (2007)Cite this article

Abstract

In this study, we extracted a polysaccharide (short-chain polysaccharide [PS]) from porcine cartilage and examined its function in chronic myeloid leukaemia by using human K562 cells and mouse L1210 cells. Results of cell proliferation assay indicated that PS inhibited cancer cell growth at different concentrations, while it had little effect on normal cells. The presence of morphological aspects of apoptosis, such as nuclear shrinkage, was shown in H&E stained sections. The occurrence of PS-induced apoptosis was confirmed by TUNEL assay and cell cycle analysis. The results of immunofluorescent staining indicated the molecular mechanism underlying. Through interfering with the cell cycle of tumor cells, PS may induce apoptosis by downregulating the expression level of cyclin D1 and upregulating the level of p21 protein. Correlation analysis of apoptosis and MAPK suggested that inactivation of ERK was crucial for PS induced apoptosis, while JNK phosphorylation had a small effect and p38 was not involved. In vivo assay showed that PS inhibited L1210 cell growth in vivo and prolonged the life span of L1210-bearing mice. We conclude that PS is a polysaccharide with anticancer effects and induced apoptosis in human K562 cells.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Abbreviations

CML:

chronic myeloid leukaemia

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

dimethyl sulfoxide

ERK:

extracellular signal-regulated kinases

H&E:

hematoxylin and eosin

ILS:

increase in lifespan

JNK:

c-jun N-terminal kinase

PS:

polysaccharide

MAPK:

mitogen-activated protein kinase

SAPK:

stress-activated protein kinase

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

References

  • Adachi S, Leoni LM, Carson DA, Nakahata T. Apoptosis induced by molecular targeting therapy in hematological malignancies. Acta Haematol 2004;111:107–23.

    PubMed  Article  CAS  Google Scholar 

  • Bandyopadhyay G, Biswas T, Roy KC, et al. Chlorogenic acid inhibits Bcr-Abl tyrosine kinase and triggers p38 mitogen-activated protein kinase-dependent apoptosis in chronic myelogenous leukemic cells. Blood 2004;104:2514–22.

    PubMed  Article  CAS  Google Scholar 

  • Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002;1:493–502.

    PubMed  Article  CAS  Google Scholar 

  • Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 1995;82:675–84.

    PubMed  Article  CAS  Google Scholar 

  • Ebina T, Fujimiya Y. Antitumor effect of a peptide-glucan preparation extracted from Agaricus blazei in a double-grafted tumor system in mice. Biotherapy 1998;11:259–65.

    PubMed  Article  CAS  Google Scholar 

  • Evered D, Whelan J. Functions of the proteoglycans. Ciba Foundation Symposium, vol. 124; 1986.

  • Fujimiya Y, Suzuki Y, Katakura R, Ebina T. Tumor-specific cytocidal and immunopotentiating effects of relatively low molecular weight products derived from the basidiomycete, Agaricus blazei Murill. Anticancer Res 1999;19:113–8.

    PubMed  CAS  Google Scholar 

  • Gao XX, Wang BX, Fei XF, et al. Effects of polysaccharides (FI0-c) from mycelium of Ganoderma tsugae on proinflammatory cytokine production by THP-1 cells and human PBMC (II). Acta Pharmacol Sin 2000;21(12):1186–92.

    PubMed  CAS  Google Scholar 

  • Hardingham TE, Fosang AJ. Proteoglycans: many forms and many functions. FASEB J. 1992;6:861–70.

    PubMed  CAS  Google Scholar 

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993;75:805–16.

    PubMed  Article  CAS  Google Scholar 

  • Im SA, Oh ST, Song S, et al. Identification of optimal molecular size of modified aloe polysaccharides with maximum immunomodulatory activity. Int Immunopharmacol 2005;5(2):271–9.

    PubMed  Article  CAS  Google Scholar 

  • Jia Fuxing, Shen Xianrong, Yu Zhijie, et al. Cartilage antitumour preparation and use in experimental cancer therapy. Chin J Biochem Pharmac 1996;17(4):150.

    Google Scholar 

  • Kaufmann SH, Gores GL. Apoptosis in cancer: cause and cure. Bioessays 2000;22:1007–17.

    PubMed  Article  CAS  Google Scholar 

  • Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–57.

    PubMed  CAS  Google Scholar 

  • Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001;81:807–69.

    PubMed  CAS  Google Scholar 

  • McGee MM, Campiani G, Ramunno A, et al. Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. J Biol Chem 2002;277:18383–9.

    Article  CAS  Google Scholar 

  • Melo JV. BCR-ABL gene variants. Bailliére's Clin Haematol 1997;10:203–22.

    CAS  Article  Google Scholar 

  • Melo JV, Deininger MW. Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004;18:545–68, vii–viii.

    PubMed  Article  Google Scholar 

  • Nakaya TA, Kita M, Kuriyama H, et al. Panax ginseng induces production of proinflammatory cytokines via toll-like receptor. J Interferon Cytokine Res 2004;24(2):93–100.

    PubMed  Article  CAS  Google Scholar 

  • Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 1994;211:90–8.

    PubMed  Article  CAS  Google Scholar 

  • Oikawa T, Ashino-Fuse H, Shimamura M, Koide U, Lwaguchi T. A novel angiogenic inhibitor derived from Japanese shark cartilage (I): extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett 1990;51:181–6.

    PubMed  Article  CAS  Google Scholar 

  • Rosenwald IB, Chen JJ, Wang S, Savas L, London LM, Pullman J. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 1999;18:2507–17.

    PubMed  Article  CAS  Google Scholar 

  • Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290–3.

    PubMed  Article  CAS  Google Scholar 

  • Santini MT, Rainaldi G, Indovina PL. Apoptosis, cell adhesion and the extracellular matrix in the three-dimensional growth of multicellular tumor spheroids. Oncol Hematol 2000;36:75–87.

    Article  CAS  Google Scholar 

  • Sherr CJ. Cancer cell cycles. Science 1996;274:1672–7.

    PubMed  Article  CAS  Google Scholar 

  • Shin JY, Song JY, Yun YS, et al. Immunostimulating effects of acidic polysaccharides extract of Panax ginseng on macrophage function. Immunopharmacol Immunotoxicol 2002;24(3):469–82.

    PubMed  Article  CAS  Google Scholar 

  • Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 1985;315:550–4.

    PubMed  Article  CAS  Google Scholar 

  • Tsiftsoglou AS, Pappas IS, Vizirianakis IS. Mechanisms involved in the induced differentiation of leukemia cells. Pharmacol Ther 2003;100:257–90.

    PubMed  Article  CAS  Google Scholar 

  • Waga S, Hannon GJ, Beach D, Stillman B. The p21 inhibitor of cyclin dependent kinases controls DNA replication by interaction with PCNA. Nature (Lond.) 1994;369:574–8.

    Article  CAS  Google Scholar 

  • Wu WT, Gao MF, Wu WJ. Progress in antimumor of polysaccharides. Chin J Nat Med 2003;1(3):181–5.

    Google Scholar 

  • Wu Y. Apoptosis and breast cancer. J Chin Cancer 1997;7(2):137–9.

    Google Scholar 

  • Yin T, Wu YL, Sun HP, et al. Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein. Blood 2004;104:4219–25.

    PubMed  Article  CAS  Google Scholar 

  • Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature(Lond.) 1999;411:1017–21.

    Article  CAS  Google Scholar 

  • Zhou Y. Progress of anti-tumor study of polysaccharide. Foreign Med 2001;28(3):129–32.

    Google Scholar 

Download references

Acknowledgments

This work was supported by grant from the National Natural Science Foundation of China (no. 20576101) and attracted faculty research start-up funding from Tianjin University of Science and Technology (no. 0200038).

Author information

Affiliations

  1. Tianjin Key Laboratory of Food Nutrition and Safety, Institute of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin, PR China

    A.-J. Liu, W. Song, N. Yang, Y.-J. Liu & G.-R. Zhang

Authors
  1. A.-J. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y.-J. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G.-R. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to A.-J. Liu or G.-R. Zhang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, AJ., Song, W., Yang, N. et al. Cartilage polysaccharide induces apoptosis in human leukemia K562 cells. Cell Biol Toxicol 23, 465–476 (2007). https://doi.org/10.1007/s10565-007-9008-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-007-9008-z

Keywords

  • Cartilage polysaccharide
  • Chronic myeloid leukaemia
  • L1210
  • Apoptosis