Specific interactions of new antitumor unsymmetrical bisacridines, UAs, with DNA and ABC proteins and their potential to modulate the enzymatic activity and trancription of nuclear receptor as the elements of their molecular mechanism of action. - Project - MOST Wiedzy

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Specific interactions of new antitumor unsymmetrical bisacridines, UAs, with DNA and ABC proteins and their potential to modulate the enzymatic activity and trancription of nuclear receptor as the elements of their molecular mechanism of action.

Considering the specific properties of our new antitumor agents,UAs, our hypothesis is based on the multidirected action of these compounds, what probably results from their extraordinary structural form in aqueous media. We suspect that this form induces the formation of G4 and remains incorporated inside. The influence on ABC transporters responsible for drug resistance is also considered. Moreover, these compounds are potent in to change enzymatic activity of P450 UGT and GST metabolic enzymes directly and/or by the influence on the activity of nuclear receptors (NR) as PXR and CAR. NRs are also able to mediate signalling in cell proliferation, apoptosis and tumor development. We are going to undertake wide investigations on UAs mechanisms of action in non-cellular systems, in the selected tumor cell lines and in animals. We will undertake several tasks: 1. Determination of 3D structure(s) of UAs in aqueous media and the description of UAs/G4 molecular interactions 2. Transcriptional effects of UAs. Evaluation of functionally relevant genes and pathways 3. Evaluation whether UAs are the substrates and/or modulators of transmembrane pumps of the ABC transporter family. 4. Metabolism of UAs in tumor cells. Their impact on the modulation of enzymatic activity in HepG2 and LS180 cells and on the expression levels of the selected P450 and UGT isoenzymes. In case of positive results from point 2, further experiments concerning the expressions and protein levels of certain nuclear receptors. 5. Cross-talk between the expression of NR and proteins involved in the cell cycle progression and apoptosis in HepG2, LS180 and DU-145 cells following bisacridines treatment. 6. The urine and blood analysis relative to metabolic kinetics of two selected new UAs in mice. The proposed studies will improve the knowledge about the potent antitumor drug, which was developed in our laboratory (Chemical Faculty, GUT) and was patented in EU (2017) and US(2019) by Gdańsk University of Technology. Therefore, we will improve the value of these compounds in the following projects leading to its introducing into clinical therapy.

Details

Project's funding:
OPUS
Agreement:
UMO-2019/33/B/NZ7/02534 z dnia 2020-04-02
Realisation period:
2020-04-02 - 2023-04-01
Project manager:
prof. dr hab. inż. Zofia Mazerska
Realised in:
Department of Pharmaceutical Technology and Biochemistry
External institutions
participating in project:
  • Clinical Research Centre, Medical University of Białystok (Poland)
Request type:
National Research Programmes
Domestic:
Domestic project
Verified by:
Gdańsk University of Technology

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