Krystyna Michalak

Publications (78) View all

• Article: Reversal of Multidrug Resistance by Natural Substances from Plants

  J. Molnar, H. Engi, J. Hohmann, P. Molnar, J. Deli, O. Wesolowska, K. Michalak, Q. Wang
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  ABSTRACT: The multidrug resistance (MDR) proteins that belong to the ATP-binding cassette superfamily such as Pglycoprotein (P-gp) and MRP1, are present in a majority of human tumors and constitute an important cause of therapeutic failure. Selective inhibitors of the MDR-efflux proteins may improve the effectiveness of cancer chemotherapy. Their mechanism of action was believed to be a competition between resistance modifiers and drugs for the same binding site of P-gp. In our previous work we studied modulation of MDR in cancer cells expressing P-gp or MRP1 by selected carotenoids, flavonoids and extracts from medically important Chinese plants. Capsanthin and capsorubin, carotenoids isolated from paprika, were identified as potent P-gp inhibitors, while lycopene, lutein, antheraxanthin and violaxanthin induced moderate effects. Among flavonoids, effective modulators were rotenone, chrysin, phloretin and sakuranetin. Some chloroform extracts of Chinese herbs were also found to inhibit MDR efflux pumps. The effects of the modulators on Pgp activity were studied by measuring rhodamine 123 uptake in several cancer cells such as the human MDR1 genetransfected mouse lymphoma cells (L1210) and human breast cancer cells MDA-MB-231 expressing the MRP1 pump (HTB26). Additionally, the ability to alter biophysical properties of lipid bilayers by selected carotenoids was studied by differential scanning calorimetry. The antiproliferative effects as well as the MDR reversal activity of the studied compounds, applied in combination with anticancer drugs, were also discussed.
  Current Topics in Medicinal Chemistry 11/2010; 10(17):1757-1768. · 4.17 Impact Factor
• Article: Reversal of multidrug resitance by natural substances from plants.

  J Molnár, H Engi, J Hohmann, P Molnár, J Deli, O Wesolowska, K Michalak, Q Wang
  [show abstract] [hide abstract]
  ABSTRACT: The multidrug resistance (MDR) proteins that belong to the ATP-binding cassette superfamily such as P-glycoprotein (P-gp) and MRP1, are present in a majority of human tumors and constitute an important cause of therapeutic failure. Selective inhibitors of the MDR-efflux proteins may improve the effectiveness of cancer chemotherapy. Their mechanism of action was believed to be a competition between resistance modifiers and drugs for the same binding site of P-gp. In our previous work we studied modulation of MDR in cancer cells expressing P-gp or MRP1 by selected carotenoids, flavonoids and extracts from medically important Chinese plants. Capsanthin and capsorubin, carotenoids isolated from paprika, were identified as potent P-gp inhibitors, while lycopene, lutein, antheraxanthin and violaxanthin induced moderate effects. Among flavonoids, effective modulators were rotenone, chrysin, phloretin and sakuranetin. Some chloroform extracts of Chinese herbs were also found to inhibit MDR efflux pumps. The effects of the modulators on P-gp activity were studied by measuring rhodamine 123 uptake in several cancer cells such as the human MDR1 gene-transfected mouse lymphoma cells (L1210) and human breast cancer cells MDA-MB-231 expressing the MRP1 pump (HTB26). Additionally, the ability to alter biophysical properties of lipid bilayers by selected carotenoids was studied by differential scanning calorimetry. The antiproliferative effects as well as the MDR reversal activity of the studied compounds, applied in combination with anticancer drugs, were also discussed.
  Current topics in medicinal chemistry 01/2010; 10(17):1757-68. · 4.47 Impact Factor
• Article: Influence of the multidrug transporter inhibitors on the activity of Kv1.3 voltage-gated potassium channels.

  A Teisseyre, N Duarte, M-J U Ferreira, K Michalak
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  ABSTRACT: Using the whole-cell patch-clamp technique, the influence of selected multidrug resistance modulators, both plant-derived compounds and derivatives on the activity of voltage-gated potassium channels Kv1.3 was investigated. Twelve compounds with phenolic and terpenic structures were tested: the stilbenes piceatannol (1) and its tetramethoxy (2) and tetracetoxy (3) derivatives, the flavonoids naringenin (4) and its methylated derivatives: naringenin-4',7-dimethylether (5) and naringenin-7-methylether (6), and aromadendrin (7), the coumarins esculetin (8) and scopoletin (9) and ent-abietane diterpenes, helioscopinolide B (10) and its 3beta-acetoxy derivative (11) and helioscopinolide E (12). The studies were performed on a model system with Kv1.3 channels endogenously expressed in human T lymphocytes. Obtained data provide evidence that compounds 2, 5 and 6 applied at 30 microM inhibited the amplitude of recorded currents to 31%, 4% and 29% of its control value, respectively. On the other hand, compounds 3, 4, 7-12 (at 30 microM) and compound 1 (at 40 microM) did not affect significantly the channel activity. These results indicate that some methoxy-derivatives of the tested compounds are effective inhibitors of Kv1.3 channels. Since the inhibition of Kv1.3 channels may inhibit the proliferation of prostate, breast and colon cancer cells expressing these channels, the channel inhibitors may exert an antiproliferative action. This action combined with a simultaneous modulation of the multidrug resistance may be significant for a potential application of these compounds in cancer chemotherapy.
  Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 04/2009; 60(1):69-76. · 2.27 Impact Factor
• Chapter: The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

  K. Michalak, O. Wesołowska, N. Motohashi, A. B. Hendrich
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  ABSTRACT: Phenothiazine derivatives as well as flavonoids belong to heterocyclic compounds that exert numerous effects on biological systems. The structure of these compounds enables their specific interactions with different membrane proteins and also nonspecific interactions with the lipid phase of membranes. In the present review we focus on the influence of phenothiazines and flavonoids on lipid bilayers and other model systems, and on two groups of membrane proteins: transporters involved in the phenomenon of multidrug resistance and ion channels. Most of the compounds described in this paper interact with membranes and affect different properties of lipid bilayers. Modification of membrane properties should contribute to mechanisms underlying certain types of biological activity of the discussed molecules. Structural features essential for the modulatory effects exerted by phenothiazines and flavonoids on multidrug transporters are presented. Also various types of response of voltage-gated and chemically activated ion channels to the presence of heterocyclic compounds are reviewed.
  05/2007: pages 223-302;
• Article: Influence of silybin on biophysical properties of phospholipid bilayers

  O. Wesołowska, B. Łania-Pietrzak, M. Kuźdźał, K. Stańczak, D. Mosiądz, P. Dobryszycki, A. Ożyhar, M. Komorowska, A. B. Hendrich, K. Michalak
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  ABSTRACT: AIM: Silybin (silibinin) is major biologically active flavonolignan extracted from milk thistle (Sylibum marianum). Its biological activities include hepato-protection, anticancer properties, and antioxidant- and membrane-stabilizing functions. Although membranes are postulated to be one of the cellular targets for silybin, little is known about its interaction with phospholipid bilayers. METHODS: In the present work, the interactions of silybin with phosphatidylcholine bilayers were studied in detail using fluorescence spectroscopy, microcalorimetry and electron spin resonance techniques. RESULTS: The results showed that silybin interacted with the surface of lipid bilayers. It affected the generalized polarization of the fluorescent probe Prodan, while not influencing the more deeply located Laurdan. Silybin lowered the main phospholipid phase transition temperature as judged by microcalorimetry, and caused the immobilization of spin probe Tempo-palmitate located on the surface of membranes. The mobility of spin probes 5- and 16-doxyl stearic acid was not affected by silybin. Silybin-induced quenching of 1,6-diphenyl-1,3,5-hexatriene fluorescence indicated that some flavonoid molecules partitioned into the hydrophobic region of membranes, which did not change significantly the biophysical properties of the deeper membrane regions. CONCLUSION: Such a behavior of silybin in membranes is in accordance with its postulated biological functions and neglectable side effects of therapies using silybin.
  Acta Pharmacol Sin. 01/2007; 28(2):296-306.