Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

Oncogene volume 22, pages 5338–5347 (2003)Cite this article

Abstract

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 μ M; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21CIP1 and p27KIP1. These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Bearss DJ, Hurley LH and Von Hoff DD . (2000). Oncogene, 19, 6632–6641.

  • Blackburn E and Greider C . (eds). (1995). Telomeres, Cold Spring Harbor Laboratory Press: New York.

    Google Scholar 

  • Blasco MA, Gasser SM and Linger J . (1999). Genes Dev., 13, 2353–2359.

  • Brown AL, Lee CH, Schwarz JK, Mitiku N, Piwnica-Worms H and Chung JH . (1999). Proc. Natl. Acad. Sci. USA, 96, 3745–3750.

  • Bryan TM, Englezou A, Gupta J, Bacchetti S and Reddel RR . (1995). EMBO J., 14, 4240–4248.

  • Chaturvedi P, Eng WK, Zhu Y, Mattern M, Mishra R, Hurle MR, Zhang Z, Annan RS, Lu Q, Faucette LF, Scott GF, Li X, Carr SA, Johson RK, Winkler JD and Zhou BBS . (1999). Oncogene, 18, 4047–4054.

  • Chaves-Dias C, Hundley TR, Gilfillan AM, Kirshenbaum AS, Cunha-Melo JR, Metcalf DD and Beaven MA . (2001). J. Immunol., 166, 6647–6656.

  • Chehab NH, Malikzay A, Appel M and Halazonetis TD . (2000). Genes Dev., 14, 278–288.

  • Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I, Priepke H, Niestroj C, Daiber C, Enenkel B, Guilliard B, Lauritsch I, Muller E, Pascolo E, Sauter G, Pantic M, Martens UM, Wenz C, Lingner J, Kraut N, Rettig WJ and Schnapp A . (2001). EMBO J., 20, 6958–6968.

  • Delhommeau F, Thierry A, Feneux D, Lauret E, Leclercq E, Courtier MH, Sainteny F, Vainchenker W and Bennaceur-Griscelli A . (2002). Oncogene, 21, 8262–8271.

  • de Lange T and Jacks T . (1999). Cell, 98, 273–275.

  • Druker BJ, Resta DJ, Peng B, Buchdunger E, Ford JM, Capdeville R and Tarpaz M . (2001). N. Engl. J. Med., 344, 1031–1037.

  • Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J and Lydon NB . (1996). Nat. Med., 2, 561–566.

  • Dunham MA, Neumann AA, Fasching CL and Reddel RR . (2000). Nat. Genet., 4, 447–450.

  • Glukhov AI, Zimnik OV, Gordeev SA and Severin SE . (1998). Biochem. Biophys. Res. Commun., 248, 368–371.

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN and Sawyers CL . (2001). Science, 293, 876–880.

  • Guiducci C, Cerone MA and Bacchetti S . (2001). Oncogene, 20, 714–725.

  • Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JHM, Meyerson M and Weinberg RA . (1999). Nat. Med., 5, 1164–1170.

  • Harley CB . (1991). Mutat. Res., 256, 271–282.

  • Hirano A, Kong YY, Matuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ and Mak TW . (2000). Science, 287, 1824–1827.

  • Hisatomi H, Nagao K, Kanamaru T, Endo H, Tomimatsu M and Hikiji K . (1999). Int. J. Oncol., 14, 727–732.

  • Izbicka E, Wheelhouse RT, Raymond E, Davidson KL, Lawrence RA, Sun D, Windle BE, Hurley LH and Von Hoff DD . (1999). Cancer Res., 59, 639–644.

  • Kharbanda S, Kumar V, Dhar S, Pandey P, Chen C, Majumder P, Yuan ZM, Whang Y, Strauss W, Pandita TK, Weaver D and Kufe D . (2000). Curr. Biol., 10, 568–575.

  • Kim MS, Rivera M, Botchkina I, Shalaby R, Thor AD and Blackburn EH . (2001). Proc. Natl. Acad. Sci. USA, 98, 7982–7987.

  • Kim MY, Vankayalapati H, Shin-ya K and Hurley LH . (2002). J. Am. Chem. Soc., 123, 1262–1263.

  • Kondo S, Kondo Y, Li G, Silverman RH and Cowell JK . (1998). Oncogene, 16, 3323–3330.

  • Lavin MF and Shiloh Y . (1997). Annu. Rev. Immunol., 15, 177–202.

  • Lee KH, Rudolph KL, Ju YJ, Greenberg RA, Cannizzaro L, Chin L, Weiler SR and DePinho RA . (2001). Proc. Natl. Acad. Sci. USA, 98, 3381–3386.

  • Liu JP . (1999). FASEB J., 13, 2091–2104.

  • Meyerson M . (2000). J. Clin. Oncol., 18, 2626–2634.

  • Nakajima A, Tauchi T and Ohyashiki K . (2001). Leukemia, 15, 989–990.

  • Nakajima A, Tauchi T, Sashida G, Sumi M, Abe K, Yamamoto K, Ohyashiki JH and Ohyashiki K . (2003). Leukemia, 17, 560–567.

  • Ohyashiki K, Miyauchi J, Ohyashiki JH, Saito M, Yaguchi M, Inatomi Y, Nakazawa S, Wada H, Mizutani S, Matsuo Y, Minowada J and Toyama K . (1993). Leukemia, 7, 1034–1040.

  • Ohyashiki JH, Sashida G, Tauchi T and Ohyashiki K . (2002). Oncogene, 21, 680–687.

  • Perry PJ and Jenkins TC . (1999). Exp. Opin. Invest. Drugs, 8, 1981–2008.

  • Sachsinger J, Gonzalez-Suarez E, Samper E, Heicappell R, Muller M and Blasco MA . (2001). Cancer Res., 61, 5580–5586.

  • Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AMR, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS and Shiloh Y . (1995). Science, 268, 1749–1753.

  • Sawyers CL, McLauglin J, Goga A, Havlik M and Witte ON . (1994). Cell, 77, 121–131.

  • Shi DN, Wheelhouse RT, Sun D and Hurley LH . (2001). J. Med. Chem., 44, 4509–4523.

  • Shieh SY, Ahn J, Tamai K, Taya Y and Prives C . (2000). Genes Dev., 14, 289–300.

  • Shin-ya K, Wierzba K, Matsuo K, Ohtani T, Yamada Y, Furihata K, Hayakawa Y and Seto H . (2001). J. Am. Chem. Soc., 123, 1262–1263.

  • Sun D, Thompson B, Cathers BE, Salazar M, Kerwin S, Trent JO, Jenkins TC, Niedle S and Hurley LH . (1997). J. Med. Chem., 40, 2113–2116.

  • Tauchi T, Feng GS, Shen R, Song HY, Donner D, Pawson T and Broxmeyer HE . (1994). J. Biol. Chem., 269, 15381–15387.

  • Tauchi T, Nakajima A, Sashida G, Shimamoto T, Ohyashiki JH, Abe K, Yamamoto K and Ohyashiki K . (2002). Clin. Cancer Res., 8, 3341–3347.

  • van Steensel B, Smogorzewska A and de Lange T . (1998). Cell, 92, 401–413.

  • Wheelhouse TR, Sun D, Han H, Han F and Hurley LH . (1998). J. Am. Chem. Soc., 120, 3261–3262.

  • Zahler AM, Williamson JR, Cech TRR and Prescotte DM . (1991). Nature, 350, 718–720.

  • Zhang X, Mar V, Zhou W, Harrington L and Robinson MO . (1999). Genes Dev., 13, 2388–2399.

Download references

Acknowledgements

This work was supported by a grant-in-aid from the Ministry of Education, Science and Culture of Japan (to TT) and NOVARTIS Foundation for the Promotion of Science (to TT) and by the Promotion and Mutual Aid Corporation for Private School of Japan (to KO) and by the high-tech research center for intractable disease of Tokyo Medical University from the Ministry of Education, Culture, Sports, Science and Technology in Japan (to KO). We thank Hisashi Hisatomi (SRL, Inc.) for analysis of telomerase activity and hTERT expression.

Author information

Authors and Affiliations

  1. First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan

    Tetsuzo Tauchi, Goro Sashida, Masahiko Sumi, Akihiro Nakajima, Takashi Shimamoto & Kazuma Ohyashiki

  2. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0032, Japan

    Kazuo Shin-ya

  3. Intractable Disease Research Center, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-0023, Japan

    Junko H Ohyashiki

Authors
  1. Tetsuzo Tauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuo Shin-ya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Goro Sashida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masahiko Sumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akihiro Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takashi Shimamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Junko H Ohyashiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuma Ohyashiki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tetsuzo Tauchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tauchi, T., Shin-ya, K., Sashida, G. et al. Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways. Oncogene 22, 5338–5347 (2003). https://doi.org/10.1038/sj.onc.1206833

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206833

Keywords

This article is cited by

Search

Advanced search

Quick links