Cell Biology of Anticancer Drug Action 


 

Head of the lab

Gábor Szabó, MD, PhD, DSc

Full Professor
E-mail:
Webpage

 

 

 

 

 

 

 

 

Staff

  • Katalin Goda, MSc, PhD, associate professor
  • László Imre, MSc, reasearch fellow
  • Péter Nánási, MD, junior research fellow
  • Erfaneh Firouzi Niaki, Dr. Pharm., PhD student
  • Rosevalentine Bosire, PhD student
  • Zsuzsanna Gyöngy, PhD student
  • Nubar Hamidova, PhD student
  • Kuljeet Singh, PhD student
  • Zsuzsanna Ritter, MSc, junior research fellow
  • Adél Nagy Vezendiné, technician
  • Lilla Szoboszlay, research student

 

 

 

 

Former members of the group

  • Tamás Varga, PhD
  • Zsolt Bacsó, MD, PhD
  • György Fenyőfalvi, MD
  • Lóránt Székvölgyi, PhD
  • Éva Hegedüs, MSc, PhD
  • Szabolcs Tarapcsák, MSc, junior research fellow
  • Henrietta Nagy, PhD
  • Ferenc Fenyvesi, PhD
  • Orsolya Bársony, PhD student
  • Gábor Szalóki, PhD 
  • Pataki Judit, MSc
  • Szilágyi Ildikó, MSc
  • Annamária Téglási, diploma student, technician
  • Beatrix Ágics, diploma student
  • Zsanett Bukó, diploma student
  • Szabó Brigitta, diploma student

 

Research topics

  • A.    Nuclear organization and chromatin structure group - Superhelical and relaxed chromatin domains
  • B.    ABC transporters - multidrug resistance

 

A.    Nuclear organization and chromatin structure group - Superhelical and relaxed chromatin domains

Our ambition is to unravel the complex relationships between nucleosome stability and organization of superhelical chromatin loops, and understand the relationships between the organizational principles seen at the nucleosomal and loop levels. We anticipate and investigate observations of therapeutic relevance for chromatin and epigenetic targeting drugs from this vantage point. 

 

Background

Nucleosomal structure is repressive for transcription, hence eukaryotic gene regulation is primarily based on de-repression at the level of the chromatin. It is fine-tuned, among other factors, by histone posttranslational modifications (PTMs), and entails and depends on negative supercoling of the DNA. In line with this global picture, supercoil relaxation elicits a strong, PTM-dependent nucleosome destabilizing effect according to our published and unpublished data. Our previous work has also led us to recognize that DNA superhelicity has a strong and direct impact on the target size and binding affinity of two major classes of anticancer drugs: DNA intercalators and interstrand-crosslinking agents. We have formulated the concept that the intertwined effects of PTMs and regulation of supercoiling are integrated at the level of nucleosome stability what may be an important overall read-out of drug effects.
 

Projects

Summary of recent publications

 

Representative publications

  • Éva Hegedüs, Endre Kókai, Péter Nánási, László Imre, László Halász, Rozenn Jossé, Zsuzsa Antunovics, Martin R. Webb, Aziz El Hage, Yves Pommier, Lóránt Székvölgyi, Viktor Dombrádi and Gábor Szabó: Endogenous single-strand DNA breaks at RNA polymerase II promoters in Saccharomyces cerevisiae. Nucleic Acids Research, in press. A summary of this publication is enclosed below. 
  • Imre L, Simándi Z, Horváth A, Fenyőfalvi G, Nánási P, Niaki EF, Hegedüs É, Bacsó Z, Weyemi U, Mauser R, Ausio J, Jeltsch A, Bonner W, Nagy L, Kimura H, Szabó G. Nucleosome stability measured in situ by automated quantitative imaging. Sci Rep. 2017 Oct 6;7(1):12734. 
  • Simandi Z, Czipa E, Horvath A, Koszeghy A, Bordas C, Póliska S, Juhász I, Imre L, Szabó G, Dezso B, Barta E, Sauer S, Karolyi K, Kovacs I, Hutóczki G, Bognár L, Klekner Á, Szucs P, Bálint BL, Nagy L. PRMT1 and PRMT8 regulate retinoic acid-dependent neuronal differentiation with implications to neuropathology. Stem Cells. 2015 Mar;33(3):726-41
  • Imre L, Balogh I, Kappelmayer J, Szabó M, Melegh B, Wanker E, Szabó G. Detection of mutations by flow cytometric melting point analysis of PCR products. Cytometry A. 2011 Sep;79(9):720-6. 
  • Hegedüs E, Kókai E, Kotlyar A, Dombrádi V, Szabó G. Separation of 1-23-kb complementary DNA strands by urea-agarose gel electrophoresis. Nucleic Acids Res. 2009 Sep;37(17):e112. 
  • Hegedüs E, Imre L, Pataki J, Lizanecz E, Székvölgyi L, Fazakas F, Bacsó Z, Tóth A, Szabó M, Seres Z, Szabó G. Heteroduplex analysis using flow cytometric microbead assays to detect deletions, insertions, and single-strand lesions. Cytometry A. 2008 Mar;73(3):238-45.
  • Székvölgyi L, Rákosy Z, Bálint BL, Kókai E, Imre L, Vereb G, Bacsó Z, Goda K, Varga S, Balázs M, Dombrádi V, Nagy L, Szabó G. Ribonucleoprotein-masked nicks at 50-kbp intervals in the eukaryotic genomic DNA. Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):14964-9. 
  • Székvölgyi L, Bálint BL, Imre L, Goda K, Szabó M, Nagy L, Szabó G. Chip-on-beads: flow-cytometric evaluation of chromatin immunoprecipitation. Cytometry A. 2006 Oct 1;69(10):1086-91. 
  • Székvölgyi L, Hegedüs E, Molnár M, Bacsó Z, Szarka K, Beck Z, Dombrádi V, Austin C, Szabó G. Nick-forming sequences may be involved in the organization of eukaryotic chromatin into approximately 50 kbp loops. Histochem Cell Biol. 2006 Jan;125(1-2):63-73. 
  • Pataki J, Szabó M, Lantos E, Székvölgyi L, Molnár M, Hegedüs E, Bacsó Z, Kappelmayer J, Lustyik G, Szabó G. Biological microbeads for flow-cytometric immunoassays, enzyme titrations, and quantitative PCR. Cytometry A. 2005 Nov;68(1):45-52. 

 

B.    ABC transporters - multidrug resistance

Background
 

Our current projects

  • Elucidation of the functional relationships between the two nucleotide binding sites of Pgp
  • Studying the functional coupling between the substrate binding sites and the nucleotide binding sites of Pgp
  • Elucidation of the conformational switch between the high and low dug binding affinity states upon the catalytic cycle of ABCG2 
  • Studying the membrane microenvironment of Pgp and ABCG2
  • Studying the interaction of Pgp and ABCG2 with anthocyanins 

Representative publications

  • Tarapcsák, S., Szalóki, G., Telbisz, Á., Gyöngy, Z., Matúz, K., Csősz, É., Nagy P.,  Holb, IJ, Rühl, R., Nagy, L., Szabó, G., Goda, K. Interactions of retinoids with the ABC transporters P-glycoprotein and Breast Cancer Resistance Protein. Sci. Rep. 7, 41376., 2017.
  • Bársony, O., Szalóki, G., Türk, D., Tarapcsák, S., Gutay-Tóth, Z., Bacsó, Z., Holb, I., Székvölgyi, L., Szabó, G., Csanády, L., Szakács, G., Goda, K.: A single active catalytic site is sufficient to promote transport in P-glycoprotein. Sci. Rep 6 (24810), 1-16., 2016.
  • Trencsényi, G., Kertész, I., Krasznai, Z., Máté, G., Szalóki, G., Péli-Szabó, J., Kárpáti, L., Krasznai, Z., Márián, T., Goda, K.: 2' [ 18F]-fluoroethylrhodamine B is a promising radiotracer to measure P-glycoprotein function. Eur. J. Pharm. Sci 74 27-35., 2015.
  • Szalóki, G., Krasznai, Z., Tóth, Á., Vízkeleti, L., Szöllősi, A., Trencsényi, G., Lajtos, I., Juhász, I., Krasznai, Z., Márián, T., Balázs, M., Szabó, G., Goda, K.: The strong in vivo anti-tumor effect of the UIC2 monoclonal antibody is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity. PloS ONE 9 (9), 1-9., 2014.
  • Krasznai, Z., Trencsényi, G., Krasznai, Z., Mikecz, P., Nizsalóczki, E., Szalóki, G., Péli-Szabó, J., Balkay, L., Márián, T., Goda, K.: 18FDG a PET tumor diagnostic tracer is not a substrate of the ABC transporter P-glycoprotein. Eur. J. Pharm. Sci 64C 1-8., 2014.
  • Krasznai, Z., Tóth, Á., Mikecz, P., Fodor, Z., Szabó, G., Galuska, L., Hernádi, Z., Goda, K.: Pgp inhibition by UIC2 antibody can be followed in vitro by using tumor-diagnostic radiotracers, 99mTc-MIBI and 18FDG. Eur. J. Pharm. Sci 41 (5), 665-669., 2010.
  • Goda, K., Bacsó, Z., Szabó, G.: Multidrug resistance through the spectacle of P-glycoprotein. Curr. Cancer Drug Targets 9 (3), 281-297., 2009.
  • Goda, K., Fenyvesi, F., Bacsó, Z., Nagy, H., Márián, T., Megyeri, A., Krasznai, Z., Juhász, I., Vecsernyés, M., Szabó, G.: Complete inhibition of P-glycoprotein by simultaneous treatment with a distinct class of modulators and the UIC2 monoclonal antibody. J. Pharmacol. Exp. Ther 320 (1), 81-88., 2007.
  • Nagy, H., Goda, K., Fenyvesi, F., Bacsó, Z., Szilasi, M., Kappelmayer, J., Lustyik, G., Cianfriglia, M., Szabó, G.: Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies. Biochem. Biophys. Res. Commun 315 (4), 942-949., 2004.
  • Goda, K., Nagy, H., Mechetner, E., Cianfriglia, M., Szabó, G.: Effects of ATP depletion and phosphate analogues on P-glycoprotein conformation in live cells. Eur. J. Biochem 269 (11), 2672-2677., 2002.
  • Goda, K., Nagy, H., Bene, L., Balázs, M., Arceci, R., Mechetner, E., Szabó, G.: Conformational heterogeneity of P-glycoprotein. Cancer Detect. Prev 24 (5), 415-421., 2000.

Updated: 2020.04.29.


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