Ellipticine cytotoxicity to cancer cell lines - a comparative study

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Ellipticine cytotoxicity to cancer cell lines - a comparative study

Ellipticine is a potent antineoplastic agent exhibiting multiple mechanisms of action. This anticancer agent should be considered a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its cytochrome P450 (CYP)- and/or peroxidase-mediated activation to species forming covalent DNA adducts. Ellipticine can also act as an inhibitor or inducer of biotransformation enzymes, thereby modulating its own metabolism leading to its genotoxic and pharmacological effects. Here, a comparison of the toxicity of ellipticine to human breast adenocarcinoma MCF-7 cells, leukemia HL-60 and CCRF-CEM cells, neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cells and U87MG glioblastoma cells and mechanisms of its action to these cells were evaluated. Treatment of all cells tested with ellipticine resulted in inhibition of cell growth and proliferation. This effect was associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by 13-hydroxy- and 12-hydroxyellipticine, the ellipticine metabolites generated by CYP and peroxidase enzymes, in MCF-7, HL-60, CCRF-CEM, UKF-NB-3, UKF-NB-4 and U87MG cells, but not in neuroblastoma UKF-NB-3 cells. Therefore, DNA adduct formation in most cancer cell lines tested in this comparative study might be the predominant cause of their sensitivity to ellipticine treatment, whereas other mechanisms of ellipticine action also contribute to its cytotoxicity to neuroblastoma UKF-NB-3 cells.

Aimová D, Svobodová L, Kotrbová V, Mrázová B, Hodek P, Hudeček J, Václavíková R., Frei E. (2007). The anticancer drug ellipticine is a potent inducer of rat cytochromes P450 1A1 and 1A2, thereby modulating its own metabolism. Drug Metab Dispos 35: 1926-1934.

Auclair C. (1987). Multimodal action of antitumor agents on DNA: The ellipticine series. Arch Biochem Biophys 259: 1-14.

Bořek-Dohalská L, Frei E and Stiborová M. (2004). DNA adduct formation by the anticancer drug ellipticine and its hydroxy derivatives in human breast adenocarcinoma MCF-7 cells. Collect Czech Chem Commun 69: 603-615.

Cinatl J Jr, Cinatl J, Driever PH, Kotchetkov R, Pouckova P, Kornhuber B and Schwabe D. (1997). Sodium valproate inhibits in vivo growth of human neuroblastoma cells. Anti-Cancer Drugs 8: 958-63.

Frei E, Bieler CA, Arlt VM, Wiessler M and Stiborová M. (2002). Covalent binding of the anticancer drug ellipticine to DNA in V79 cells transfected with human cytochrome P450 enzymes. Biochem Pharmacol 64: 289-295.

Garbett NC and Graves DE. (2004). Extenting nature's leads: the anticancer agent ellipticine. Curr Med Chem Anti-Cancer Agents 4: 149-72.

Huska D, Adam V, Krizkova S, Hrabeta J, Eckschlager T, Stiborova M and Kizek R. (2010a) An electrochemical study of interaction of an anticancer alkaloid ellipticine with DNA. Chim Oggi-Chem Today 28(5) Suppl S: 15-17.

Huska D, Adam V, Hubalek J, Trnkova L, Eckschlager T, Stiborova M, Provaznik I and Kizek R. (2010b). Off-line coupling of automated pipetting system with square wave voltammetry as a tool for study of drug-DNA interaction. Chim Oggi-Chem Today 28:(5) Suppl S: 18-20.

Fossé P, René B, Charra M, Paoletti C and Saucier JM. (1992). Stimulation of topoisomerase II-mediated DNA cleavage by ellipticine derivatives: structure-activity relationships. Mol Pharmacol 42: 590-595.

Froelich-Ammon SJ, Patchan MW, OsheroffN and Thompson RB. (1995). Topoisomerase II binds to ellipticine in the absence or presence of DNA. Characterization of enzyme-drug interactions by fluorescence spectroscopy. J Biol Chem 270: 4998-5004.

Kuo PL, Hsu YL, Chang CH and Lin CC. (2005a). The mechanism of ellipticineinduced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells. Cancer Lett 223: 293-301.

Kuo PL, Hsu YL, Kuo YC, Chang CH and Lin CC. (2005b). The antiproliferative inhibition of ellipticine in human breast mda-mb-231 cancer cells is through cell cycle arrest and apoptosis induction. Anti-Cancer Drugs 16: 789-795.

Kuo PL, Kuo YC, Hsu YL, Cho CY and Lin CC. (2006). Ellipticine induced apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. Life Sci. 78: 2550-2557.

Martinkova E, Dontenwill M, Frei E and Stiborova M. (2009). Cytotoxicity of and DNA adduct formation by ellipticine in human U87MG glioblastoma cancer cells. Neuro Endocrinol Lett 30 (Suppl 1): 60-66.

Martinkova E, Maglott A, Leger, DY, Bonnet D, Stiborova M, Takeda K, Martin S and Dontenwill M. (2010). α5β1 integrin antagonists reduce chemotherapy-induced premature senescence and facilitate apoptosis in human glioblastoma cells. Int J Cancer 127: 1240-1248.

McCormick DL, Adamowski CB, Fiks A, Moon RC. (1981). Lifetime dose-response relationships for mammary tumor induction by a single administration of N-methyl-N-nitrosourea, Cancer Res 41: 1690-1694.

Monnot M, Mauffret O, Simon V, Lescot E, Psaume B, Saucier JM, Charra M, Belehradek J Jr and Fermandjian S. (1991). DNA-drug recognition and effects on topoisomerase II-mediated cytotoxicity. A three-mode binding model for ellipticine derivatives. J Biol Chem 25: 1820-1829.

Moserová M, Kotrbová V, Rupertová M, Naiman K, Hudeček J, Hodek P, Frei E and Stiborová M. (2008). Isolation and partial characterization of the adduct formed by 13-hydroxyellipticine with deoxyguanosine in DNA. Neuro Endocrinol Lett. 29: 728-732.

Ohashi M, Sugikawa E and Nakanishi N. (1995). Inhibition of p53 protein phosphorylation by 9-hydroxyellipticine: A possible anticancer mechanism. Jpn J Cancer Res 86: 819-829.

Poljaková J, Dračínský M, Frei E., Hudeček J and Stiborová M. (2006). The effect of pH on peroxidase-mediated oxidation of and DNA-adduct formation by ellipticine. Collect Czech Chem Commu. 71: 1169-1185.

Poljaková J, Frei E, Gomez JE, Aimová D, Eckschlager T, Hraběta J and Stiborová M. (2007). DNA adduct formation by the anticancer drug ellipticine in human leukemia HL-60 and CCRF-CEM cells. Cancer Lett 252: 270-279.

Poljaková J, Eckschlager T, Hraběta J, Hřebačková J, Smutný S, Frei E, Martínek V, Kizek R and Stiborová M. (2009). The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells. Biochem Pharmacol 77: 1466-1479.

Singh MP, Hill GC, Peoch D, Rayner, B, Inabach, JL and Lown JW. (1994). Highfield NMR and restrained molecular modeling studies on a DNA heteroduplex containing a modified apurinic abasic site in the form of covalently linked 9-aminoellipticine. Biochemistry 33: 10271-10285.

Stiborová M, Bieler CA, Wiessler M and Frei E. (2001). The anticancer agent ellipticine on activation by cytochrome P450 forms covalent DNA adducts. Biochem Pharmacol 62: 675-684.

Stiborová M, Breuer A, Aimová D, Stiborová-Rupertová M, Wiessler M and Frei E. (2003a). DNA adduct formation by the anticancer drug ellipticine in rats determined by 32P-postlabeling. Int J Cancer 107: 885-890.

Stiborová M, Stiborová-Rupertová M, Bořek-Dohalská L, Wiessler M, Frei E. (2003b). Rat microsomes activating the anticancer drug ellipticine to species covalently binding to deoxyguanosine in DNA are a suitable model mimicking ellipticine bioactivation in humans. Chem Res Toxicol 16: 38-47.

Stiborová M, Sejbal J, Bořek-Dohalská L, Aimová D, Poljaková J, Forsterová K, Rupertová M, Wiesner J, Hudeček J, Wiessler M and Frei E. (2004). The anticancer drug ellipticine forms covalent DNA adducts, mediated by human cytochromes P450, through metabolism to 13-hydroxyellipticine and ellipticine N2-oxide. Cancer Res 64: 8374-8380.

Stiborová M, Rupertová M. Schmeiser HH and Frei E. (2006). Molecular mechanism of antineoplastic action of an anticancer drug ellipticine. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 150: 13-23.

Stiborová M, Poljaková J, Ryšlavá H, Dračínský M, Eckschlager T and Frei E. (2007a). Mammalian peroxidases activate anticancer drug ellipticine to intermediates forming deoxyguanosine adducts in DNA identical to those found in vivo and generated from 12-hydroxyellipticine and 13-hydroxyellipticine. Int J Cancer 120: 243-251.

Stiborová M, Rupertová M, Aimová D, Ryšlavá H and Frei E. (2007b). Formation and persistence of DNA adducts of anticancer drug ellipticine in rats. Toxicology 236: 50-60.

Stiborová M, Arlt VM, Henderson CJ, Wolf CR, Kotrbová V, Moserová M, Hudeček J, Phillips DH and Frei E. (2008). Role of hepatic cytochromes P450 in bioactivation of the anticancer drug ellipticine: studies with the hepatic NADPH:cytochrome P450 reductase null mouse. Toxicol Appl Pharmacol 226: 318-327.

Stiborová M, Rupertová M and Frei E. (2011). Cytochrome P450- and peroxidase-mediated oxidation of anticancer alkaloid ellipticine dictates its antitumor efficiency. Biochim Biophys Acta 1814: 175-185.

Sugikawa E, Hosoi T, Yazaki N, Gamanuma N, Nakanishi N and Ohashi M. (1999). Mutant p53 mediated induction of cell cycle arrest and apoptosis at G1 phase by 9-hydroxyellipticine. Anticancer Res 19: 3099-3108.

Interdisciplinary Toxicology

The Journal of Institute of Experimental Pharmacology of Slovak Academy of Sciences

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CiteScore 2017: 2.36

SCImago Journal Rank (SJR) 2017: 0.580
Source Normalized Impact per Paper (SNIP) 2017: 1.134

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