Skip to main content
SpringerLink
Log in

Ortho-topolin riboside induces apoptosis in Acute myeloid leukemia HL-60 cells

  • Original Paper
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

6-(2-hydroxybenzylamino)-9-D-ribofuranosylpurine (ortho-topolin riboside, oTR), a naturally occurring cytokinin and nucleoside analog has potential anticancer effects. However, the molecular mechanisms remain elusive. We found that oTR strongly inhibited Acute myeloid leukemia HL-60 cell proliferation, altered the cell cycle, induced cytochrome c release from mitochondria into the cytosol, and increased caspase-3 activity. Apoptosis was confirmed by DNA ladder formation following gel electrophoresis. These results indicated that oTR induced apoptosis through activation of the intrinsic mitochondrial pathway. Moreover, the apoptosis was significantly suppressed by the adenosine transporter inhibitor dipyridamole and adenosine kinase inhibitor A-134974. These data indicated that cellular uptake of oTR was an active process involving an adenosine transporter, and subsequently phosphorylated by an adenosine kinase. Taken together, Our study suggests that oTR is taken up by HL-60 cells, converted to the phosphorylated form, and induces apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Santini, V. et al. Butyrate-stable monosaccharide derivatives induce maturation and apoptosis in human acute myeloid leukaemia cells. Br J Haematol 101:529–538 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Ewald, B., Sampath, D. & Plunkett, W. Nucleoside analogs: Molecular mechanisms signaling cell death. Oncogene 27:6522–6537 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Jordheim, L. P., Durantel, D., Zoulim, F. & Dumontet, C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 12:447–464 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Honma, Y. Control of differentiation and apoptosis of human myeloid leukemia cells by cytokinins and cytokinin nucleosides, plant redifferentiation-inducing hormones. Drug Develop Res 56:560–560 (2002).

    Google Scholar 

  5. Voller, J. et al. Anticancer activity of natural cytokinins: A structure-activity relationship study. Phytochemistry 71:1350–1359 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Berge, U., Kristensen, P. & Rattan, S. I. S. Kinetin-induced differentiation of normal human keratinocytes undergoing aging in vitro. Ann N Y Acad Sci 1067:332–336 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Ishii, Y., Sakai, S. & Honma, Y. Cytokinin-induced differentiation of human myeloid leukemia hl-60 cells is associated with the formation of nucleotides, but not with incorporation into DNA or RNA. Biochim Biophys Acta 1643:11–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Mlejnek, P. Caspase inhibition and n6-benzyladenosine-induced apoptosis in hl-60 cells. J Cell Biochem 83:678–689 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Choi, B. H. et al. Kinetin riboside preferentially induces apoptosis by modulating bcl-2 family proteins and caspase-3 in cancer cells. Cancer Lett 261:37–45 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Cabello, C. M. et al. The experimental chemotherapeutic n6-furfuryladenosine (kinetin-riboside) induces rapid atp depletion, genotoxic stress, and cdkn1a(p21) upregulation in human cancer cell lines. Biochem Pharmacol 77:1125–1138 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Griffaut, B., Bos, R., Maurizis, J. C., Madelmont, J. C. & Ledoigt, G. Cytotoxic effects of kinetin riboside on mouse, human and plant tumour cells. Int J Biol Macromol 34:271–275 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Laezza, C. et al. N6-isopentenyladenosine inhibits cell proliferation and induces apoptosis in a human colon cancer cell line dld1. Int J Cancer 124:1322–1329 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Meisel, H., Gunther, S., Martin, D. & Schlimme, E. Apoptosis induced by modified ribonucleosides in human cell culture systems. FEBS Lett 433:265–268 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Spinola, M., Colombo, F., Falvella, F. S. & Dragani, T. A. N6-isopentenyladenosine: A potential therapeutic agent for a variety of epithelial cancers. Int J Cancer 120:2744–2748 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Laezza, C. et al. N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation. FASEB J 20:412–418 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Tiedemann, R. E. et al. Identification of kinetin riboside as a repressor of ccnd1 and ccnd2 with preclinical antimyeloma activity. J Clin Invest 118:1750–1764 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Mittelman, A., Evans, J. T. & Chheda, G. B. Cytokinins as chemotherapeutic-agents. Ann Ny Acad Sci 255:225–234 (1975).

    Article  CAS  PubMed  Google Scholar 

  18. Hewett, E. W. & Wareing, P. F. Cytokinins in populus x robusta schneid -complex in leaves. Planta 112:225–233 (1973).

    Article  CAS  PubMed  Google Scholar 

  19. Cano-Soldado, P. & Pastor-Anglada, M. Transporters that translocate nucleosides and structural similar drugs: Structural requirements for substrate recognition. Med Res Rev 32:428–457 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Prathapan, A., Vineetha, V. P. & Raghu, K. G. Protective effect of boerhaavia diffusa l. Against mitochondrial dysfunction in angiotensin ii induced hypertrophy in h9c2 cardiomyoblast cells. Plos One 9 (2014).

  21. Minuesa, G. et al. Drug uptake transporters in antiretroviral therapy. Pharmacol Ther 132:268–279 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Mok, M. C., Martin, R. C. & Mok, D. W. S. Cytokinins: Biosynthesis, metabolism and perception. In Vitro Cell Dev-Pl 36:102–107 (2000).

    Article  CAS  Google Scholar 

  23. Javadov, S. et al. Antihypertrophic effect of na+/h+ exchanger isoform 1 inhibition is mediated by reduced mitogen-activated protein kinase activation secondary to improved mitochondrial integrity and decreased generation of mitochondrial-derived reactive oxygen species. J Pharmacol Exp Ther 317:1036–1043 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Javadov, S. & Karmazyn, M. Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem 20:1–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Javadov, S., Karmazyn, M. & Escobales, N. Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. J Pharm Exp Ther 330:670–678 (2009).

    Article  CAS  Google Scholar 

  26. Matsumoto, S., Friberg, H., Ferrand-Drake, M. & Wieloch, T. Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion. J Cerebr Blood F Met 19:736–741 (1999).

    Article  CAS  Google Scholar 

  27. Hu, W. & Kavanagh, J. J. Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 4:721–729 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Spierings, D. et al. Connected to death: The (unexpurgated) mitochondrial pathway of apoptosis. Science 310:66–67 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Liu, X. et al. Molecular basis for g2 arrest induced by 2’-c-cyano-2’-deoxy-1-beta-d-arabino-pentofuranosylcytosine and consequences of checkpoint abrogation. Cancer Res 65:6874–6881 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Chen, Y. H. & Sanchez, Y. Chk1 in the DNA damage response: Conserved roles from yeasts to mammals. DNA Repair 3:1025–1032 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Shi, Z. et al. S-phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine. Cancer Res 61:1065–1072 (2001).

    CAS  PubMed  Google Scholar 

  32. Wang, J., Li, X. R., Liu, Y. B. & Zhao, X. Salt stress induces programmed cell death in thellungiella halophila suspension-cultured cells. J Plant Physiol 167:1145–1151 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, L., Sun, C., Wang, Z. H. & Guo, G. Q. Mechanism of apoptotosis induced by ortho-topolin riboside in human hepatoma cell line smmc-7721. Food Chem Toxicol 50:1962–1968 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Life and Medicine, Dalian University of Technology, Panjin, Liaoning, 124221, P.R, China

    Li Wang, Dong Li Yu, Han Wen Zhang & Lei Yu He

  2. Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou, Gansu, 730000, P.R, China

    Lei Wu

Authors
  1. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dong Li Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han Wen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Yu He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Wang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Yu, D.L., Zhang, H.W. et al. Ortho-topolin riboside induces apoptosis in Acute myeloid leukemia HL-60 cells. Mol. Cell. Toxicol. 12, 159–166 (2016). https://doi.org/10.1007/s13273-016-0020-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-016-0020-3

Keywords

Search

Navigation