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Liquid crystal-related compound-induced cell growth suppression and apoptosis in the chronic myelogenous leukemia K562 cell line

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Summary

Liquid crystals are the state of matter existing between the liquid and the crystalline phase, and there is a recent surging interest in its biological effects. Our previous study showed that liquid crystal-related compounds (LCRCs), which are precursors of the liquid crystal, enhanced hematopoietic differentiation at a relatively low concentration (Biol Pharm Bull, 32, 2009). However, biological potentials of LCRCs on tumor cells are unclear. In this study, the biological activity of 16 LCRCs to a chronic myelogenous leukemia cell line, K562, was evaluated. As a result, two compounds, 2-(4-butoxyphenyl)-5-(4-hydroxyphenyl)pyrimidine (compound 7) and 2-{4-(4-hexyloxyphenyl)phenyl}-5-hydroxypyrimidine (compound 9) showed marked growth suppression of K562 cells at μM range. These compounds are similar in structure with a core of three aromatic rings including a pyrimidine ring and residues of one alkyl chain and one hydroxide on either side. In addition, only compound 7 induced the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, and apoptosis of K562 cells. The contrasting results between compounds 7 and 9 indicate different mechanisms to suppress the cell proliferation between the two compounds. These results suggest the possibility of LCRCs for application as new antitumor drugs.

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References

  1. Uga H, Kuramori C, Ohta A, Tsuboi Y, Tanaka H, Hatakeyama M, Yamaguchi Y, Takahashi T, Kizaki M, Hanada H (2006) A new mechanism of methotrexate action revealed by target screening with affinity beads. Mol Pharm 70:1832–1839

    Article  CAS  Google Scholar 

  2. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev 7:573–584

    Article  CAS  Google Scholar 

  3. Wang SY, Weiner G (2008) Complement and cellular cytotoxicity in antibody therapy of cancer. Expert Opin Biol Ther 8:759–768

    Article  PubMed  CAS  Google Scholar 

  4. Perez EA (2009) Microtubule inhibitors: differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther 8:2086–2095

    Article  PubMed  CAS  Google Scholar 

  5. Metzger-Filho O, Moulin C, De Azambuja E, Ahamad A (2009) Larotaxel: broadening the road with new taxanes. Expert Opin Investig Drugs 18:1183–1189

    Article  PubMed  CAS  Google Scholar 

  6. Skobridis K, Kinigopoulou M, Theodorou V, Giannousi E, Russell A, Chauhan R, Sala R, Brownlow N, Kiriakdis S, Domin J, Tzakos AG, Dibb NJ (2010) Novel imatinib derivatives with altered specificity between bcr-abl and FMS, KIT, and PDGF receptors. Chem Med Chem 5:130–139

    PubMed  CAS  Google Scholar 

  7. Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T (1994) Bcr-Abl oncoproteins bind directly to activators of the Ras signaling pathway. EMBO J 13:764–773

    PubMed  CAS  Google Scholar 

  8. Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B (1997) Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 16:6151–6161

    Article  PubMed  CAS  Google Scholar 

  9. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042

    Article  PubMed  CAS  Google Scholar 

  10. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, WT WE, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug reasistance. Biochim Biophys Acta 1773:1263–1284

    Article  PubMed  CAS  Google Scholar 

  11. Fava C, Kantarjian H, Cortes J, Jabbour E (2008) Development and targeted use of nilotinib in chronic myeloid leukemia. Drug Des Devel Ther 2:223–243

    Google Scholar 

  12. Hazlehurst LA, Bewry NN, Nair RR, Pinilla-lbarz J (2009) Signaling networks associated with bcr-abl-dependent transformation. Cancer Control 16:100–107

    PubMed  Google Scholar 

  13. Hochhaus A, Schenk T, Erben P, Ernst T, Rosée P, Müller M (2009) Cause and management of therapy resistance. Best Pract Res Clin Haematol 22:577–582

    Article  Google Scholar 

  14. Stevenson CL, Bennet DB, Lechuga-Ballesteros D (2005) Pharmaceutical liquid crystals: the relevance of partially ordered systems. J Pharm Sci 94:1861–1880

    Article  PubMed  CAS  Google Scholar 

  15. Dymond MK, Attard GS (2008) Cationic Type І amphiphiles as modulators of membrane curvature elastic stress in vivo. Langmuir 24:11743–11751

    Article  PubMed  CAS  Google Scholar 

  16. Terasawa R, Fukushi Y, Monzen S, Miura T, Takahashi K, Yoshizawa A, Kashiwakura I (2009) The promoting activity on human megakaryocytopoiesis and thrombopoiesis by liquid crystal-related compounds. Biol Pharm Bull 32:976–981

    Article  PubMed  CAS  Google Scholar 

  17. Hazawa M, Wada K, Takahashi K, Mori T, Kawahara N, Kashiwakura I (2009) Suppressive effects of novel derivatives prepared from aconitum alkaloids on tumor growth. Invest New Drugs 27:111–119

    Article  PubMed  CAS  Google Scholar 

  18. Kirk KL (2006) Selective fluorination in drug design and development: an overview of biochemical rationales. Curr Top Med Chem 6:1447–1456

    Article  PubMed  CAS  Google Scholar 

  19. Crocker PJ, Mahadevan A, Wiley JL, Martin BR, Razdan RK (2007) The role of fluorine substitution in the structure–activity relationships (SAR) of classical cannabinoids. Bioorg Med Chem Lett 17:1504–1507

    Article  PubMed  CAS  Google Scholar 

  20. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinase on apoptosis. Science 270:1326–1331

    Article  PubMed  CAS  Google Scholar 

  21. Zhang G, Fu Y (2006) Antiproliferative effect of indomethacin on CML cells is related to the suppression of STATs/Bcl-xL signal pathway. Ann Hematol 85:443–449

    Article  PubMed  CAS  Google Scholar 

  22. Yang SH, Chien CM, Lu MC, Lin YH, Hu XW, Lin SR (2006) Up-regulation of Bax and endonuclease G, and down-modulation of Bcl-xL involved in cardiotoxin III-induced apoptosis in K562 cells. Exp Mol Med 38:435–444

    PubMed  CAS  Google Scholar 

  23. Meng Y, Li Y, Li J, Li H, Fu J, Liu Y, Liu H, Chen X (2007) (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leuk Lymphoma 48:2204–2212

    Article  PubMed  CAS  Google Scholar 

  24. Liu MJ, Li HX, Wu RC, Liu YZ, Wu QY (2004) Mitochondrial dysfunction as an early event in the process of apoptosis induced by woodfordin Iin human leukemia K562 cells. Toxicol Appl Pharm 194:141–155

    Article  CAS  Google Scholar 

  25. Mao X, Yu CR, Li WH, Li WX (2008) Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. Cell Res 18:879–888

    Article  PubMed  CAS  Google Scholar 

  26. Yoshizawa A, Takahashi Y, Terasawa R, Shota C, Takahashi K, Haawa M, Kashiwakura I (2009) Liquid crystallinity and biological activity of a novel amphiphilic compound. Chem Lett 38:310–311

    Article  CAS  Google Scholar 

  27. Yoshizawa A, Takahashi Y, Terasawa R, Shota C, Takahashi K, Haawa M, Kashiwakura I (2009) Biological activity of some cyanobiphenyl derivatives. Chem Lett 38:530–531

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant for Hirosaki University Institutional Research (2008–2009) and by a Grant-in-Aid for Challenging Exploratory Research from Japan Society for the Promotion of Science (No. 21655045).

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Authors and Affiliations

  1. Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, 036-8564, Japan

    Ikuo Kashiwakura

  2. Department of Frontier Materials Chemistry, Graduate School of Science and Technology, Hirosaki University, 3 Bunkyo-cho, Hirosaki, 036-8561, Japan

    Yukako Fukushi & Atsushi Yoshizawa

  3. Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan

    Masaharu Hazawa & Kenji Takahashi

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  1. Yukako Fukushi
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  2. Masaharu Hazawa
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  3. Kenji Takahashi
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  4. Atsushi Yoshizawa
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  5. Ikuo Kashiwakura
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Correspondence to Ikuo Kashiwakura.

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Fukushi, Y., Hazawa, M., Takahashi, K. et al. Liquid crystal-related compound-induced cell growth suppression and apoptosis in the chronic myelogenous leukemia K562 cell line. Invest New Drugs 29, 827–832 (2011). https://doi.org/10.1007/s10637-010-9430-6

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  • DOI: https://doi.org/10.1007/s10637-010-9430-6

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