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Apoptosis of Human Burkitt’s lymphoma cells induced by 2-N,N-Diethylaminocarbonyloxymethyl-1-diphenylmethyl-4-(3,4,5-trimethoxybenzoyl) piperazine hydrochloride (PMS-1077)

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Abstract

Piperazine is one of the heterocycles which are associated with diverse pharmacological activities. 2-N,N-Diethylaminocarbonyloxymethyl-1-diphenylmethyl-4-(3,4,5-trimethoxybenzoyl) piperazine hydrochloride (PMS-1077) is a trisubstituted piperazine which contains a trimethoxybenzene ring and a benzhydrylpiperazine fragment, both of which can induce cell proliferation regression by different mechanisms. We have therefore examined the effects of PMS-1077 on Human Burkitt’s lymphoma cells (Raji). The viability of Raji cells was determined by MTT assay and also assessed by trypan blue dye exclusion method. The results demonstrate that PMS-1077 can suppress the proliferation of Raji cells in a dose- and timedependent manner, while inhibit colony formation ability of Raji cells merely in a dose-dependent manner in vitro. Meanwhile, morphological changes were observed using fluorescence microscope. Flow cytometric analysis through PI stains showed that PMS-1077 blocked the growth of Raji cells in the G0/G1 period, and induced apoptosis of Raji cells after 48 h of incubation. Cell apoptosis induced by PMS-1077 was further confirmed by staining with Annexin-V FITC and PI. Preliminary study by molecular docking suggests that PMS-1077 may inhibit tubulin polymerization. More experiments are in progress in our laboratory to reveal the mode of action of PMS-1077 in the induction of apoptosis of Raji cells.

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References

  • A Orjales, J. G.-S., L Alonso-Cires, L Labeaga, R Mosquera, a Berisa, M Ucelay, a Innerarity, R Corcostegui Synthesis and histamine HI-receptor antagonist activity of 4-(diphenylmethyl)-1-piperazine derivatives with a terminal heteroaryl or cycloalkyl amide fragment. Eur. J. Med Chem., 31, 813–818 (1996).

    Article  CAS  Google Scholar 

  • Alvarez, C., Alvarez, R., Corchete, P., Lopez, J. L., Perez-Melero, C., Pelaez, R., and Medarde, M., Diarylmethyloxime and hydrazone derivatives with 5-indolyl moieties as potent inhibitors of tubulin polymerization. Bioorg Med. Chem., 16, 5952–5961 (2008a).

    Article  CAS  PubMed  Google Scholar 

  • Alvarez, C., Alvarez, R., Corchete, P., Perez-Melero, C., Pelaez, R., and Medarde, M., Naphthylphenstatins as tubulin ligands: synthesis and biological evaluation. Bioorg. Med. Chem., 16, 8999–9008 (2008b).

    Article  CAS  PubMed  Google Scholar 

  • Bellosillo, B., Pique, M., Barragan, M., Castano, E., Villamor, N., Colomer, D., Montserrat, E., Pons, G., and Gil, J., Aspirin and salicylate induce apoptosis and activation of caspases in B-cell chronic lymphocytic leukemia cells. Blood, 92, 1406–1414 (1998).

    CAS  PubMed  Google Scholar 

  • Bernhard, D., Schwaiger, W., Crazzolara, R., Tinhofer, I., Kofler, R., and Csordas, A., Enhanced MTT-reducing activity under growth inhibition by resveratrol in CEMC7H2 lymphocytic leukemia cells. Cancer Lett., 195, 193–199 (2003).

    CAS  PubMed  Google Scholar 

  • Bremer, E., Van Dam, G., Kroesen, B. J., De Leij, L., and Helfrich, W., Targeted induction of apoptosis for cancer therapy: current progress and prospects. Trends Mol Med., 12, 382–393 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Cheng, X. C., Liu, X. Y., Xu, W. F., Guo, X. L., and Ou, Y., Design, synthesis, and biological activities of novel Ligustrazine derivatives. Bioorg. Med. Chem., 15, 3315–3320 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Darzynkiewicz, Z., Bruno, S., Del Bino, G., Gorczyca, W., Hotz, M. A., Lassota, P., and Traganos, F., Features of apoptotic cells measured by flow cytometry. Cytometry, 13, 795–808 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Delano, W. L., PyMol Molecular Graphics System, DeLano Scientific (2002).

  • Doudican, N., Rodriguez, A., Osman, I., and Orlow, S. J., Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol. Cancer Res., 6,1308–1315 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Garrett, M., Morris, D. S. G., Robert S. Halliday, Ruth Huey, William E. Hart, Richard K. Belew, Arthur J., Olson automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J. Comput Chem., 19, 1639–1662 (1998).

    Article  Google Scholar 

  • Ghobrial, I. M., Witzig, T. E., and Adjei, A. A., Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin., 55, 178–194 (2005).

    Article  PubMed  Google Scholar 

  • Ghosh, P., Besra, S. E., Tripathi, G., Mitra, S., and Vedasiromoni, J. R., Cytotoxic and apoptogenic effect of tea (Camellia sinensis var. assamica) root extract (TRE) and two of its steroidal saponins TS1 and TS2 on human leukemic cell lines K562 and U937 and on cells of CML and ALL patients. Leuk. Res., 30, 459–468 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Guex, N., and Peitsch, M. C., SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis, 18, 2714–2723 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Hoessel, R., Leclerc, S., Endicott, J. A., Nobel, M. E., Lawrie, A., Tunnah, P., Leost, M., Damiens, E., Marie, D., Marko, D., Niederberger, E., Tang, W., Eisenbrand, G., and Meijer, L., Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat. Cell Biol., 1, 60–67 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Jiang, J. D., Davis, A. S., Middleton, K., Ling, Y. H., Perez-Soler, R., Holland, J. F., and Bekesi, J. G., 3-(Iodoacetamido)-benzoylurea: a novel cancericidal tubulin ligand that inhibits microtubule polymerization, phosphorylates bcl-2, and induces apoptosis in tumor cells. Cancer Res., 58, 5389–5395 (1998).

    CAS  PubMed  Google Scholar 

  • Joseph, B., Lewensohn, R., and Zhivotovsky, B., Role of apoptosis in the response of lung carcinomas to anticancer treatment. Ann. N. Y. Acad. Sci., 926, 204–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Kasibhatla, S. and Tseng, B., Why target apoptosis in cancer treatment? Mol. Cancer Ther., 2, 573–580 (2003).

    CAS  PubMed  Google Scholar 

  • Kerr, J. F., Winterford, C. M., and Harmon, B. V., Apoptosis. Its significance in cancer and cancer therapy. Cancer, 73, 2013–2026 (1994).

    Article  CAS  PubMed  Google Scholar 

  • Kiechle, F. L. and Zhang, X., Apoptosis: biochemical aspects and clinical implications. Clin. Chim. Acta., 326, 27–45 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Koopman, G., Reutelingsperger, C. P., Kuijten, G. A., Keehnen, R. M., Pals, S. T., and Van Oers, M. H., Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood, 84, 1415–1420 (1994).

    CAS  PubMed  Google Scholar 

  • Krysko, D. V., Vanden Berghe, T., D’herde, K., and Vandenabeele, P., Apoptosis and necrosis: detection, discrimination and phagocytosis. Methods, 44, 205–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Kumar, C. S., Prasad, S. B., Vinaya, K., Chandrappa, S., Thimmegowda, N. R., Kumar, Y. C., Swarup, S., and Rangappa, K. S., Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines. Eur. J. Med. Chem. (2008).

  • Lau, C. B., Ho, C. Y., Kim, C. F., Leung, K. N., Fung, K. P., Tse, T. F., Chan, H. H., and Chow, M. S., Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis. Life Sci., 75, 797–808 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Lin, C. M., Ho, H. H., Pettit, G. R., and Hamel, E., Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin. Biochemistry, 28, 6984–6991 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Los, M., Burek, C. J., Stroh, C., Benedyk, K., Hug, H., and Mackiewicz, A., Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design. Drug Discov. Today, 8, 67–77 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Lu, M. C., Yang, S. H., Hwang, S. L., Lu, Y. J., Lin, Y. H., Wang, S. R., Wu, Y. C., and Lin, S. R. Induction of G2/M phase arrest by squamocin in chronic myeloid leukemia (K562) cells. Life Sci., 78, 2378–2383 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Makin, G. and Hickman, J. A., Apoptosis and cancer chemotherapy. Cell Tissue Res., 301, 143–152 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Mantovani, A., Marchesi, F., Porta, C., Sica, A., and Allavena, P., Inflammation and cancer: breast cancer as a prototype. Breast, 16Suppl 2, S27–33 (2007).

    Article  PubMed  Google Scholar 

  • Martelli, A. M., Zweyer, M., Ochs, R. L., Tazzari, P. L., Tabellini, G., Narducci, P., and Bortul, R., Nuclear apoptotic changes: an overview. J. Cell. Biochem., 82, 634–646 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Martin, M., Serradji, N., Dereuddre-Bosquet, N., Le Pavec, G., Fichet, G., Lamouri, A., Heymans, F., Godfroid, J. J., Clayette, P., and Dormont, D., PMS-601, a new plateletactivating factor receptor antagonist that inhibits human immunodeficiency virus replication and potentiates zidovudine activity in macrophages. Antimicrob. Agents Chemother., 44, 3150–3154 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Mchugh, P. and Turina, M., Apoptosis and necrosis: a review for surgeons. Surg. Infect. (Larchmt), 7, 53–68 (2006).

    Article  Google Scholar 

  • Miao, R., Han, Y., An, L., Yang, J., and Wang, Q., Selenopodophyllotoxin derivatives induce hepatoma SMMC-7721 cell apoptosis through Bax pathway. Cell Biol. Int., 32, 217–223 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Owa, T., Okauchi, T., Yoshimatsu, K., Sugi, N. H., Ozawa, Y., Nagasu, T., Koyanagi, N., Okabe, T., Kitoh, K., and Yoshino, H., A focused compound library of novel N-(7-indolyl)benzenesulfonamides for the discovery of potent cell cycle inhibitors. Bioorg. Med. Chem. Lett, 10, 1223–1226 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., and Ferrin, T. E., UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem., 25, 1605–1612 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Rosin, M. P., Anwar, W. A., and Ward, A. J., Inflammation, chromosomal instability, and cancer: the schistosomiasis model. Cancer Res., 54, 1929s–1933s (1994).

    CAS  PubMed  Google Scholar 

  • Sallem, W., Serradji, N., Dereuddre-Bosquet, N., Dive, G., Clayette, P., and Heymans, F., Structure-activity relationships in platelet-activating factor. Part 14: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 activity. Bioorg. Med Chem., 14, 7999–8013 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Samaha, H. S., Kelloff, G. J., Steele, V., Rao, C. V., and Reddy, B. S., Modulation of apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and promotion. Cancer Res., 57, 1301–1305 (1997).

    CAS  PubMed  Google Scholar 

  • Saraste, A. and Pulkki, K., Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res., 45, 528–537 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Schmitt, C. A. and Lowe, S. W., Apoptosis and therapy. J Pathol., 187, 127–137 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Sellers, W. R. and Fisher, D. E., Apoptosis and cancer drug targeting. J. Clin. Invest., 104, 1655–1661 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Serradji, N., Bensaid, O., Martin, M., Kan, E., Dereuddre-Bosquet, N., Redeuilh, C., Huet, J., Heymans, F., Lamouri, A., Clayette, P., Dong, C. Z., Dormont, D., and Godfroid, J. J., Structure-activity relationships in platelet-activating factor (PAF). 10. From PAF antagonism to inhibition of HIV-1 replication. J. Med. Chem., 43, 2149–2154 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Serradji, N., Bensaid, O., Martin, M., Sallem, W., Dereuddre-Bosquet, N., Benmehdi, H., Redeuilh, C., Lamouri, A., Dive, G., Clayette, P., and Heymans, F., Structureactivity relationships in platelet-activating factor. Part 13: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 or pure antiretroviral activity. Bioorg. Med. Chem., 14, 8109–8125 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Serradji, N., Martin, M., Bensaid, O., Cisternino, S., Rousselle, C., Dereuddre-Bosquet, N., Huet, J., Redeuilh, C., Lamouri, A., Dong, C. Z., Clayette, P., Scherrmann, J. M., Dormont, D., and Heymans, F., Structure-activity relationships in platelet-activating factor. 12. Synthesis and biological evaluation of platelet-activating factor antagonists with anti-HIV-1 activity. J. Med. Chem., 47,6410–6419 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Sgonc, R. and Gruber, J., Apoptosis detection: an overview. Exp. Gerontol., 33, 525–533 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Surh, Y. J., Hurh, Y. J., Kang, J. Y., Lee, E., Kong, G., and Lee, S. J., Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells. Cancer Lett., 140, 1–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Thompson, C. B., Apoptosis in the pathogenesis and treatment of disease. Science, 267, 1456–1462 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A. E., and Berendsen, H. J., GROMACS: fast, flexible, and free. J. Comput. Chem., 26, 1701–1718 (2005).

    Article  CAS  Google Scholar 

  • Vermeulen, K., Van Bockstaele, D. R., and Berneman, Z. N., Apoptosis: mechanisms and relevance in cancer. Ann Hematol., 84, 627–639 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Wang, X., Wei, Y., Yuan, S., Liu, G., Zhang, Y. L., and Wang, W., Potential anticancer activity of litchi fruit pericarp extract against hepatocellular carcinoma in vitro and in vivo. Cancer Lett., 239, 144–150 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Wilson, M. R., Apoptosis: unmasking the executioner. Cell Death Differ., 5, 646–652 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Ye, C. L., Liu, J. W., Wei, D. Z., Lu, Y. H., and Qian, F., In vitro anti-tumor activity of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone against six established human cancer cell lines. Pharmacol. Res., 50, 505–510 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Yuan, S. L., Wei, Y. Q., Wang, X. J., Xiao, F., Li, S. F., and Zhang, J., Growth inhibition and apoptosis induction of tanshinone II-A on human hepatocellular carcinoma cells. World J. Gastroenterol, 10, 2024–2028 (2004).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Cancer Biology and Drug Screening, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China

    Wen-di Wang, Xi-ming Xu, Ying Chen, Peng Jiang, Chang-zhi Dong & Qin Wang

  2. Maitre de Conferences, Laboratoire de Pharmacochimie Moléculaire, Université Paris Diderot Paris 7, 15, rue Jean de Baïf, 75205, Paris Cedex 13, France

    Chang-zhi Dong

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  1. Wen-di Wang
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  2. Xi-ming Xu
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  3. Ying Chen
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  4. Peng Jiang
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  5. Chang-zhi Dong
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Correspondence to Chang-zhi Dong or Qin Wang.

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Wen-di Wang and Xi-ming Xu contributed equally to this work.

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Wang, Wd., Xu, Xm., Chen, Y. et al. Apoptosis of Human Burkitt’s lymphoma cells induced by 2-N,N-Diethylaminocarbonyloxymethyl-1-diphenylmethyl-4-(3,4,5-trimethoxybenzoyl) piperazine hydrochloride (PMS-1077). Arch. Pharm. Res. 32, 1727–1736 (2009). https://doi.org/10.1007/s12272-009-2210-1

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