Laboratory of Experimental Therapy

Laboratory of Experimental Therapy

We have been fostering multidisciplinary research at the interface of  biology, medicine, chemistry and computer science in anti-tumor drug-discovery area.

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DNA damage is a result of cell metabolic activity but also a result of environmental exposure to mutagens and as such is the main cause of tumor incidence. On the other hand, introducing DNA damage, both via irradiation and/or chemotherapy, remains the principal choice in the treatment of cancer. Furthermore, the research for elucidation of novel antiproliferative chemotherapeutics, protein targets and signaling pathways for potential treatment has been increasing over the years within the biomedical scientific community.

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LET activities are divided into two main areas, covering treatment oriented but also basic cancer biology research. In first, in vitro screening of the antiproliferative activity of newly synthesized compounds is performed on a panel of tumor cell lines with selection and profound examination of active compounds. In latter, the role of p21WAF1/Cip1, one of main genes activated after the DNA damage that usually arrests the cell cycle, is investigated on its ability to initiate and modulate different cell death mechanisms, namely apoptosis, cellular senescence, mitotic catastrophe and autophagy.

In vitro screening of novel compounds for their antiproliferative activity on tumor cells.

We have developed an in vitro/in silico platform for screening of potential novel antitumor compounds. We perform a routine in vitro screening on the antiproliferative ability of newly synthesized compounds according to the model presented at the Developmental Therapeutics Program, National Cancer Institute, National Institute of Health (DTP, NCI-NIH). These preliminary screenings are mostly made on the collaborative-bases with numerous groups dealing with the synthesis of novel anticancer drugs (from Croatia and abroad), but also on the service-basis. Besides, in collaboration with the Laboratory for Information Systems, Division of Electronics, RBI (Head: Dr. T. Šmuc) we have been establishing the computerization of data gathering, storage and analysis processes during in vitro activity measurements. We also integrate these results with available data from the DTP-NCI and apply supervised machine learning to differential cell line activities to predict biochemical mechanism of action or uncover possible cellular targets for novel compounds. 

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Since we are studying the activity of novel potential antitumor compounds (mostly small molecules) that interact with DNA/RNA, we collaborate with the Laboratory for Study of Interactions of Biomacromolecules (Head Dr. Ivo Piantanida), who perform detailed spectroscopic study of the interactions of novel compounds with the smallest (and consequently best defined) parts of the DNA/RNA, still comprising the essential properties of complete DNA/RNA targeted in the design of the substance being tested. These methods are often great help in predicting and monitoring of the experiments in the complex biological systems.

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Also, especially active/selective newly synthesized compounds are being further studied by more sophisticated molecular biology methods in order to more closely elucidate their mechanisms of action.

Katja Ester
PhD

Research associate
1772 1285

Marijeta Kralj
PhD

Senior scientist
+385 1 457 1235
1789 1773

Marko Marjanović
PhD

Research associate
1772 1285
MultiCaST Work Packages scheme

A multidisciplinary approach to discover selective drugs targeting cancer stem cells: The role of potassium transport - MultiCaST

Glavni istraživač / voditelj: Marijeta Kralj

The main goal of the proposed research is to understand cancer stem cell (CSC) biology and to develop novel CSC-directed compounds. We will strive to elucidate the molecular basis of potassium ion transport involvement in CSC-phenotype acquisition, modulation and targeting and identify key mechanisms of these processes as novel biomarkers for improved diagnostic options and innovative mechanism-based therapeutic approaches.

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  1. Perin, N; Uzelac, L; Piantanida, I; Karminski-Zamola, G; Kralj, M*; Hranjec, M*. Novel biologically active nitro and amino substituted benzimidazo[1, 2-a]quinolines. Bioorg. Med. Chem. 19 (2011) 6329-6339
  2. Ester K*, Supek F, Majsec K, Marjanović M, Lembo D, Donalisio M, Smuc T, Jarak I, Karminski-Zamola G, Kralj M. Putative mechanisms of antitumor activity of cyano-substituted heteroaryles in HeLa cells. Invest new drug. (2011), in press,
  3. Supek, F; Šumanovac Ramljak, T; Marjanović, M; Buljubašić, M; Kragol, G; Ilić, Na; Šmuc, T; Zahradka, D; Mlinarić-Majerski, K*; Kralj, M*. Could LogP be a principal determinant of biological activity in 18-crown-6 ethers? Synthesis of biologically active adamantane-substituted diaza-crowns. Eur J Med Chem. 46 (2011) 3444-3454,
  4.  Ester, K; Hranjec, M; Piantanida, I; Ćaleta, I; Ivana, J; Pavelić, K; Kralj, M*; Karminski-Zamola, G*. Novel Derivatives of Pyridyl-Benzo[b]thiophene-2-carboxamides and Benzo[b]thieno[2, 3- c]naphthyridin-2-ones: Minor Structural Variations Provoke Major Differences of Antitumor Action Mechanisms. J Med Chem. 52:2482-2492 (2009).
  5.  Ćaleta, I; Kralj, M*; Marjanović, M; Bertoša, B; Tomić, S; Pavlović, G; Pavelić, K; Karminski-Zamola, G*. Novel Cyano- and Amidino- Benzothiazole Derivatives: Synthesis, Antitumor Evaluation, X-ray and QSAR Analysis. J Med Chem. (2009) 52:1744-1756.
  6.  Kraljević Pavelić S, Čačev, T, Kralj, M. A dual role of p21waf1/cip1 gene in apoptosis of HEp-2 treated with cisplatin or methotrexate. Cancer Gene Therapy. 15 (2008) 576-590
  7.  Kraljević Pavelić, S*; Marjanović, M*; Poznić, M; Kralj, M. Adenovirally-mediated p53 overexpression diversely influence the cell cycle of HEp-2 and CAL 27 cell lines upon cisplatin and methotrexate treatment. J Cancer Res Clin Oncol. (2009) *-equal contribution
  8.  Supek, F*;Kralj, M*;Marjanović, M; Šuman, L; Šmuc, T; Krizmanić, I; Žinić, B. Atypical cytostatic mechanism of N -1-sulfonylcytosine derivatives determined by in vitro screening and computational analysis. Invest New drugs. (2008) 26:97-110. * - equal contribution
  9.  Kralj, M*; Tušek-Božić, Lj; Frkanec, L. Biomedical Potentials of Crown Ethers: Prospective Antitumor Agents. ChemMedChem. (2008) 3:1478-1492
  10.  Hranjec, M; Piantanida, I; Kralj, M; Šuman, L; Pavelić, K; Karminski-Zamola, G. Novel amidino-substituted thienyl- and furyl-vinyl-benzimidazole derivatives and their photochemical conversion into corresponding diaza-cyclopenta[c]fluorenes. Synthesis, interactions with DNA and RNA and antitumor evaluation. Part 4. J Med Chem. (2008) 51:4899-4910.
  11. Marjanović M, Kralj M*, Supek F, Frkanec L, Piantanida I, Šmuc T, Tušek-Božić Lj. Antitumor potential of crown ethers: structure activity relationships, cell cycle disturbances and cell death studies of a series of ionophores. J Med Chem (2007) 50:1007-1018
  12. Hranjec, M; Kralj, M*; Piantanida, I; Sedić, M; Šuman, L; Pavelić, K; Karminski-Zamola, G*. Novel cyano- and amidino-substituted derivatives of styryl-2-benzimidazoles and benzimidazo[1, 2-a]quinolines. Synthesis, photochemical synthesis, DNA binding, and antitumor evaluation, part 3. J Med Chem. (2007) 50:5696
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