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 acronym:

BisMolMechZM2020

Financial Program Name:

OPUS

Organization:

Narodowe Centrum Nauki (NCN) (National Science Centre)

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

Team members:

Coordination of the studies in the field of biological response of tumor cells. dr hab. Ewa Augustin
The tasks in the field of enzyme gene expression modulation and cell transport. dr inż. Monika Pawłowska
Studies on the mechanism of DNA G-quadruplexes stabilisation by the studied compounds. dr hab. inż. Tomasz Laskowski
The synthesis of the appropriate amounts of the studied bisacridine derivatives/ dr inż. Ewa Paluszkiewicz
The tasks in the field of drug cytotoxicity, drug metabolism and nuclear receptor induction. dr Joanna Frąckowiak
The tasks on the cellular level related to metabolism and cellular response. Jolanta Kulesza
Studies in the field of physicochemical properties and drug metabolism in noncellular systems. Michał Kosno

Realised in:

Department of Pharmaceutical Technology and Biochemistry

External institutions participating in project:

Clinical Research Centre, Medical University of Białystok (Poland)

Project's value:

3 011 700.00 PLN

Request type:

National Research Programmes

Domestic:

Domestic project

Verified by:

Gdańsk University of Technology

Papers associated with that project

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total: 3

Year 2022

Acid–Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis
Publication
- M. Kosno
- T. Laskowski
- J. Frąckowiak
- A. Potęga
- A. Kurdyn
- W. Andrałojć
- J. Borzyszkowska-Bukowska
- K. Szwarc-Karabyka
- Z. Mazerska
- MOLECULES - Year 2022
Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected 3D cancer spheroid growth and their cellular uptake was selectively modulated by quantum dots. UAs were shown to undergo metabolic...

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c-Myc Protein Level Affected by Unsymmetrical Bisacridines Influences Apoptosis and Senescence Induced in HCT116 Colorectal and H460 Lung Cancer Cells
Publication
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES - Year 2022
Unsymmetrical bisacridines (UAs) are highly active antitumor compounds. They contain in their structure the drugs previously synthesized in our Department: C-1311 and C-1748. UAs exhibit different properties than their monomer components. They do not intercalate to dsDNA but stabilize the G-quadruplex structures, particularly those of the MYC and KRAS genes. Since MYC and KRAS are often mutated and constitutively expressed in cancer...

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Year 2021

Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells
Publication
- A. Mieszkowska
- A. M. Nowicka
- A. Kowalczyk
- A. Potęga
- M. Pawłowska
- M. Kosno
- E. Augustin
- Z. Mazerska
- Pharmaceuticals - Year 2021
New unsymmetrical bisacridines (UAs) demonstrated high activity not only against a set of tumor cell lines but also against human tumor xenografts in nude mice. Representative UA compounds, named C-2028, C-2045 and C-2053, were characterized in respect to their physicochemical properties and the following studies aimed to elucidate the role of metabolic transformations in UAs action. We demonstrated with phase I and phase II enzymes...

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