Antimutagenic activity of new analogues of fluphenazine

• Autorzy: Gasiorowski K , Malinka W. , Swiatek P. , Jaszczyszyn A.
• Języki publikacji: EN

Abstrakty

EN

Fluphenazine (FPh) exhibited antimutagenic activity in lymphocyte cultures, markedly decreasing genotoxic effects of standard mutagenic agents present in cell cultures. However, the strong pharmacological activity of this neuroleptic drug, together with its serious side effects on the central nervous system, limits its use as an antimutagenic compound. In this paper we describe a route of chemical synthesis of FPh analogues that are more hydrophilic than the model compound, thus probably penetrate more weakly through the blood-brain barrier. These new analogues were tested for their antimutagenic and pro-apoptotic activities in human lymphocyte cultures, genotoxically damaged in vitro with benzo[a]pyrene [40 μM, 30 min] and subsequently cultured for 48 h in the presence of the tested compounds. The fluphenazine analogues enhanced apoptosis in genotoxically damaged lymphocytes more strongly than the model compound did. The increase of apoptotic cell frequency was the highest with compound 4a [2-(trifluoromethyl)-10-[3-(diethanolamino)-2-hydroxypropyl] phenothiazine] - a 35% higher effect than that of fluphenazine. The cytotoxicity of derivative 4a was the lowest among the tested compounds; it was 60% lower than that of fluphenazine. The antimutagenic effect of 4a was about 10% stronger than that of fluphenazine. Compund 4a also had the highest hydrophilicity of the new FPh analogues. Compound 4a was chosen for further study as a potentially usable antimutagen that would only weakly penetrate the central nervous system.

Słowa kluczowe

EN

pharmacological activity; fluphenazine; neuroleptic drug; antimutagenic activity; lymphocyte; new analogue; mutagenic agent; apoptosis; central nervous system; cell culture; genotoxic effect

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2003
• Tom: 08
• Numer: 4
• Opis fizyczny: p.927-942,fig.

Twórcy

autor

Gasiorowski K

• Wroclaw Medical University, Wroclaw, Poland

autor

Malinka W.

autor

Swiatek P.

autor

Jaszczyszyn A.

Bibliografia

• 1.DeFlora, S. Mechanisms of inhibitors of mutagenesis and carcinogenesis. Mutat. Res. 402 (1998) 151-158.
• 2.Kondo, S. Apoptotic repair of genotoxic tissue damage and the role of p53 gene. Mutat. Res. 402 (1998) 311-319.
• 3.Damton, S.J. Demistyfied p53. Mol. Patol. 51 (1998) 248-253.
• 4.Evan, G. and Littlewood, T. A matter of life and death. Science 281 (1998) 1317-1322.
• 5.Wang, W.X. Role of p53 in apoptosis and carcinogenesis. Anticancer Res. 19 (1999) 4759-4771.
• 6.Jones, G.R.N. Cancer therapy: phenothiazines in an unexpected role. Tumori 71 (1985) 563-569.
• 7.Gąsiorowski, K. Antimutagenic activity of todralazine and fluphenazine. A comparison of the results from short-term cytogenetic tests. Cell. Mol. Biol. Lett. 5 (2000) 397-403.
• 8.Gąsiorowski, K., Brokos, B., Szyba, K. and Leszek, J. Antimutagenic activity of fluphenazine in short-term tests. Mutagenesis 16 (2001) 31-38.
• 9.Gąsiorowski, K., Brokos, B., Kulma, A., Ogorzałek, A. and Skórkowska, K. Impact of four antimutagens on apoptosis in genotoxically damaged lymphocytes in vitro. Cell. Mol. Biol. Lett. 6 (2001) 649-675.
• 10.Gąsiorowski, K. Antimutagenesis and anticarcinogenesis. II. A comparison of the results obtained in vitro with the newly recognized antimutagenic compounds. Adv. Clin. Exp. Med. 10 (2001) 407-427.
• 11.Leuschner, J., Schafer, H. and Leuschner, F. 3-(Acyloxy)propanolamines: agents with β-adrenergic blocking activity. Eur. J. Med. Chem. 29 (1994) 241-243.
• 12.Hofman, F.M., Kanesberg, B. and Smith, D. Stability of T- and B-cell numbers in human peripheral blood. Amer. J. Clin. Pathol. 77 (1982) 710-712.
• 13.Martin, S.J., Reutelingsperger, C.P., McGahon, A.J., Rader, J.A., vanSchie, R.C., LaFace, D.M. and Green, D.R. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J. Exp. Med. 182 (1995) 1545-1556.
• 14.van Engeland, M., Nieland, L.J.W., Ramaekers, F.C.S., Schutte, B. and Reutelingsperger, C.P.M. Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31 (1998) 1-9.
• 15.Bossy-Wetzel, E. and Green, D.R. Detection of apoptosis by Annexin V. Methods Enzymol. 322 (2000) 15-39.
• 16.Lee, T.-K., Wiley, A.L., Means, J.A. and Biggs, L. Preservation of cytoplasm in the human lymphocyte micronucleus assay. Mutagenesis 9 (1994) 559-562.
• 17.Campbell, M.J. and Machin, D. Correlation and regression. In: Medical Statistics (Campbell, M.J. and Machin, D., Eds.), 2nd edition, John Willey and Sons Ltd., Chichester, New York, Brisbane, Toronto, Singapore, 1994, 69-104.
• 18.Schreier, S., Malheiros, S.V.P. and de Paula, E. Surface active drugs: Self-association and interaction with membranes and surfactants. Physicochemical and biological aspects. Biochim. Biophys. Acta 1508 (2000) 210-234.
• 19.Hendrich, A.B., Wesołowska, O. and Michalak, K. Differences and similarities in the influence of trifluoroperazine on the phase transitions of phosphatidylcholine and phosphatidylethanolamine. Curr. Top. Biophys. 25 (2001) 67-69.
• 20.Hendrich, A.B., Wesołowska, O., Komorowska, M., Motohashi, N. and Michalak, K. The alterations of lipid bilayer fluidity induced by newly synthesized phenothiazine derivative. Biophys. Chem. 98 (2002) 275-285.
• 21.Agasosler, A.V., Tungodden, L.M., Cejka, D., Bakstad, E., Sydnes, L.K. and Holmsen, H. Chropromazine-induced increase of dipalmityolphospha-tidylserine surface in monolayer at room temperature. Biochem. Pharmacol. 61 (2001) 817-825.
• 22.Hendrich, A. B., Wesołowska, O., Poła, A., Motohashi, N., Molnar J. and Michalak K. Neither lipophilicity nor membrane-perturbing potency of phenothiazine maleates correlate with the ability to inhibit P-glycoprotein transport activity. Mol. Membrane Biol. 20 (2003) 53-60.
• 23.Michalak, K., Hendrich, A.B., Wesołowska, O., Poła, A., Łania-Pietrzak, B., Motohashi, N., Shirataki, Y. and Molnar, J. Lipid perturbation caused by some isoflavones and phanothiazines, and the activity of these compounds as inhibitors of multidrug resistance. Cell. Mol. Biol. Lett. 7 (2002) 293.
• 24.Wesołowska, O., Hendrich, A.B., Motohashi, N. and Michalak, K. Phenothiazine maleates - putative MDR modifiers - decrease the fluidity of model phosphatidylserine membranes. Cell. Mol. Biol. Lett. 6 (2001) 427.
• 25.Wesołowska, O., Hendrich, A.B., Motohashi, N. and Michalak, K. A new phenothiazine derivative alters the fluidity and thermotropic behaviour of phosphatidylcholine model membranes. Cell. Mol. Biol. Lett. 7 (2002) 303.
• 26.Rici, A. and Amenta, F. Dopamine D-5 receptors in human peripheral blood lymphocytes: a radioligand binding study. J. Neuroimmunol. 53 (1994) 1-7.
• 27.Santabroggio, L., Lipartini, M., Bruni, A. and Dal Toso, R. Dopamine receptors on human T- and B-lymphocytes J. Neuroimmunol. 45 (1993) 113-119.
• 28.Bondy, B., deJonge, S., Pander, S., Primbs, J. and Ackenhail, M. Identification of dopamine D4 receptor mRNA in circulating human lymphocytes using nested polymerase chain reaction. J. Neuroimmunol. 71 (1996) 139-144.
• 29.Rici, A., Veglio, F. and Amenta, F. Radioligand binding characterization of putative dopamine D3 receptor in human peripheral blood lymphocytes with [3H]7-OH-DPAT. J. Neuroimmunol. 58 (1996) 139-144.
• 30.Amenta, F., Bronzetti, E., Felici, L., Rici, A. and Tayebati, S.K. Dopamine D2-like receptors on human lymphocytes: a radioligand binding assay and immunocytochemical study. J. Auton. Pharmacol. 19 (1999) 151-159.
• 31.Simpson, C.S. and Morris, B.J. Haloperidol and fluphenazine induce junB gene expression in rat striatum and nucleus accumbens. J. Neurochem. 63 (1994) 1955-1961.
• 32.Huff, R.M. Signal transduction pathways modulated by the D2 subfamily of dopamine receptors. Cell. Signal. 8 (1996) 453-459.
• 33.Vigh, L., Maresca, B. and Harwood, J.L. Does the membrane’s physical state control the expression of heat shock and other genes? Trends Biochem. Sci. 23 (1998) 369-374.
• 34.Gąsiorowski, K., Brokos, B. and Tabaka, H. Evaluation of the immunomodulatory activity of four compounds exerting antimutagenic effects on human lymphocytes in vitro. Cell. Mol. Biol. Lett. 5 (2000) 469-481.
• 35.Teisseyre, A. and Michalak, K. The voltage- and time-dependent blocking effect of trifluoroperazine on T lymphocyte Kv1.3 channels. Biochem. Pharmacol. 65 (2003) 551-561.
• 36.Lewis, R., and Cahalan, M. Potassium and calcium channels in lymphocytes. Ann. Rev. Immunol. 13 (1995) 623-653.
• 37.Ashkenazy-Sakhar, M. and Beitner, R. Effect of Ca-ionophore A23187 and calmodulin antagonists on regulatory mechanisms of glycolysis and cell viability of NIH-3T3 fibroblasts. Mol. Genet. Metab. 67 (1999) 334-342.
• 38.Fanger, C., Ghanshani, S., Longsdon, N., Rauer, H., Kalman, K., Zhou, J., Beckingham, K., Chandy, K., Calahan, M. and Aiyar, J. Calmodulin mediates calcium-dependent activation of the intermediate-conductance K(Ca) channel IKCa1. J. Biol. Chem. 274 (1999) 5746-5754.
• 39.Wang, J., Moreira, K.M., Campos, B., Kaetzel, M.A. and Dedman, J.R. Targeted neutralization of calmodulin in the nucleus blocks DNA synthesis and cell cycle progression. Biochim Biophys. Acta 1313 (1996) 223-228.
• 40.Karmakar, P., Natarajan, A.T., Poddar, R.K. and Dasgupta, U.B. Induction of apoptosis by phenothiazine derivatives in V79 cells. Toxicol. Lett. 125 (2001) 19-28.
• 41.Nagy, S., Aryelan, G., Molnar, J., Kawase, M. and Motohashi, N. Antitumor activity of phenothiazine-related compounds. Anticancer Res. 16 (1996) 1915-1918.
• 42.Tanaka, M., Molnar, J. and Kidd, S. Antimutagenicity of phenothiazine-metal co-ordination complexes in chemically induced mutagenesis. Anticancer Res. 17 (1997) 381-386.
• 43.Motohashi, N., Kawase, M., Saito, S. and Sakagami, H. Antitumor potential and possible targets of phenothiazine-related compounds. Curr. Drug Targets 1 (2000) 237-245
• 44.Ford, J.M. Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur. J. Cancer 32A (1996) 991-1001.
• 45.Michalak, K., Hendrich, A.B., Wesołowska, O. and Poła, A. Compounds that modulate multidrug resistance in cancer cells. Cell. Mol. Biol. Lett. 6 (2001) 362-368.
• 46.Hendrich, A.B. and Michalak, K. Lipids as a target for drugs modulating multidrug resistance of cancer cells. Curr. Drug Targets 4 (2003) 23-30.
• 47.Wesołowska, O., Molnar, J., Motohashi, N. and Michalak, K. Inhibition of P- glycoprotein transport function by N-acylphenothiazines. Anticancer Res. 22 (2002) 2863-2867.
• 48.Krishna, R. and Mayer, L.D. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur. J. Pharm. Sci. 11 (2000) 265-283.
• 49.Kawamura, K., Grabowski, D., Krivacic, K., Hidaka, H. and Ganapathi, R. Cellular events involved in the sensitization of etoposide-resistant cells by inhibitor of calcium-calmodulin-dependent processes. Biochem, Pharmacol. 52 (1996) 1903-1909.