Intercellular nonreceptor signaling; biological activity of protein kinase inhibitors under carcinogenesis

Previous and Current Research

1. Discovery of nonreceptor intercellular signaling;
2. Membranotropic activity of bioregulators including protein kinase inhibitors and nanostructures;
3. Cytophysiological effects of biologically active substances including protein kinase inhibitors, plant oils and nanostructures under carcinogenesis and inflammation;
4. Biosafety of pesticides and other pollutants.

Today the main areas of our interest are study the impact of cytostatics pyrrol derivatives on the digestive, excretory, reproductive, hematopoietic systems, as well as on the proliferative activity normal and transformed cells in vivo.

Colorectal cancer treatment in Ukraine accompanied by difficulties because of few approved cytostatic drugs, and in fact no personalized therapy. The problem of targeted therapeutics, approved for colorectal cancer treatment, is their specificity to growth factor receptors, and when the violation occurs in downstream signal pathways, the role of the receptors (and their blocking) becomes non-significant. Thus more than 40% of patients with colorectal tumors are insensitive to targeted therapy. So the design and discovery of targeted anticancer therapeutics are warranted.

The success of protein kinase inhibitors in the treatment of cancer showcased their therapeutic potential. Recently a series of protein kinases inhibitors pyrrol derivates were designed in silico and synthesized at Biological active substances interdept. Lab (on the basis of Chemistry Dept.) of Taras Shevchenko National University. As we have shown, some of them - 1-(4-chlorobenzyl)-3-Cl-4-(CF3-phenylamyno)-1Н-pyrrol-2,5-dione (called MI-1) and 5-amyno-4-(1,3-benzothyazol-2-yl)-1-(3-methoxyphenyl)-1,2-dihydro-3H- pyrrol-3-one (called D1) have cytostatic activity in vitro (cell lines of human colorectal adenocarcinoma COLO205, SW-620), and anti-tumor activity in vivo (1,2-dimethylhydrazine-induced rat colon cancer model).

Figure 1. Examples of colon tumors and quantitative characteristics of colorectal tumor growth under influence of cytostatics.

These compounds also help to reduce the inflammation of the colon lining, which accompanied tumor development, protect the liver against carcinogen-induced lesions and reveal antioxidant properties. Moreover, these agents display no severe injuries of the digestive, reproductive, hematopoietic and excretory systems after prolonged use, so could be considered as relatively safe.

Our current research is devoted to investigation of the antiinflammatory properties of pyrrol derivatives.

Inflammatory bowel diseases (IBD), consisting of Crohn's disease and ulcerative colitis, are common chronic immune mediated diseases of unknown aetiology. The main strategy of IBD treatment aimed to attenuate the bowel inflammation and to inhibit abnormal cell proliferation which takes place due to bowel lining regeneration. The basic UC therapy depends on the severity of the disease and includes anti-inflammatory drugs, in particular 5-aminosalicylic acid derivates, corticosteroids, immunosuppressors. However, traditional drugs have a number of adverse effects. Moreover, standard therapies fail to induce remission in about 30% of patients and possess the relative inefficacy to its maintenance. Thus, the discovery of the drug that would be effective as UC treatment and should have a minimum of side effects after prolonged use is a relevant.

We know that the consequence of activation of growth signaling pathways (PI3K/Akt, NFkB, Jak/STAT), in addition to the induction of cell proliferation and survival, are pro-inflammatory effect. Furthermore, the roles of inflammation and oxidative stress in tumor initiation and progression are acknowledged, as well as their close relationship. So we propose the antiinflammatory and antioxidant effects of MI-1 on IBD model.

Figure 2. Macrophotographs of bowel internal sides of rats experienced colitis under Prednisolone and MI-1 impact. A - Control, B - Colitis, C - Colitis+Prednisolone, D - Colitis+MI-1

Future Projects and Goals

• To investigate the effects of biologically active substances of nature (plant oils) and artificial (nanostructures) origin on the organism under IBD;
• To design and investigate the complexes based on pyrrol derivatives and nanostructures to reduce the effective doses and negative impact of them on the organism;
• To develop novel low-toxic anti-UC therapeutic, which also could effectively prevent and/or treat colorectal cancer, and to perform its preclinical research.

Methodological and Technical Expertise

• Common field/lab techniques in cytology, histology, biochemistry, physiology, biophysics;
• Light/fluorescent/electron microscopy;
• Xenobiotics environmental risk assessment;
• Supervising of PhD and postdoctoral students;
• Reviewing and editing of scientific manuscripts (reviewer, member of editorial board, Chief Editor of specialized journals);
• Member of Ukrainian Physiological, Ukrainian biochemical and Ukrainian Toxicological Societies;
• Member of International Academy of Cardiovascular Sciences and The New York Academy of Sciences 

Selected Publications