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New inorganic and organic molecular inhibitors of cancer cells proliferation, the mechanisms of action


Author: Garbuz Olga
Degree:doctor of biology
Speciality: 03.00.04 - Biochemistry
Year:2021
Scientific adviser: Aurelian Gulea
doctor habilitat, professor, Moldova State University
Scientific consultant: Valentin Gudumac
doctor habilitat, professor, Nicolae Testemitanu State University of Medicine and Pharmacy of the Republic of Moldova
Institution: Moldova State University

Status

The thesis was presented on the 19 February, 2021
Approved by NCAA on the 27 April, 2021

Abstract

Adobe PDF document – 1.20 Mb / in romanian
Adobe PDF document – 0.90 Mb / in english

Thesis

CZU 57.085.23:615.28

Adobe PDF document 5.66 Mb / in english
172 pages

Keywords

anticancer compound, antiproliferative activity, human cancer cell line, selective activity, antioxidant activity, hemolysis.

Summary

The thesis consists of introduction, four chapters, general conclusions and recommendations, 204 references, 5 annexes, 129 pages, 41 figures, 8 schemes, 6 tables. The results are published in 28 scientific publications (7 articles, 4 patents, 14 theses at conferences, 3 innovations).

Field of study:Nature Sciences The aim of the thesis: elucidation of the effect of the new molecular inhibitors based on organic and complex compounds on the proliferation of human cancer cell lines in comparison with such anticancer drugs as doxorubicin and cis-dichlorodiammineplatinum; determination of the inhibitors action mechanism. The objectives of the thesis: detection of the antiproliferative activity of the tested substances CMT-22, CMT-67, CMT-68, CMJ-23, CMJ-33 on the cancer cells HeLa, BxPC-3, MeW-164, RD; testing substances against normal kidney epithelial cell line MDCK in order to detect selective cytotoxicity; identification of the mechanism of inhibition of the cancer cell proliferation by the test substances; in vitro assessment of the probability of development and the nature of possible side effects of the tested substances associated with hemolysis and the formation of methemoglobin in human erythrocytes; determination of the toxicity of substances.

Novelty and relevance of the study: methods for studying the biological activity of substances were adapted; antiproliferative and antioxidant activities of five synthetic compounds (tiosemicarbazones and Cu(lI) coordination compounds with tiosemicarbazones) were determined; it was established in vitro that the investigated substances do not cause the formation of methemoglobin and do not increase the index of hemolysis in human erythrocytes; a method for determining direct toxicity using Paramecium was developed, and the direct toxicity of the investigated substances was assessed; the mechanism of the effect of the substances on the proliferation of cancer cells was revealed; the tested compounds are of interest from the point of view of their use as less toxic and more effective anticancer agents.

Scientific problem solved in this thesis is the identification of new inhibitors of cancer cells proliferation with high selective activity and lower toxicity compared to FDA-approved reference anticancer compounds (DOXO and CDDP), as well as the elucidation of the mechanism of antiproliferative action of the tested compounds. The antioxidant action of organic and inorganic molecular inhibitors on radicals (ABTS•+, DPPH•, HO2•) was determined. It has been found that the tested compounds do not cause the formation of methemoglobin and do not increase the index of hemolysis in human erythrocytes.

The theoretical importance and potential application value of the work. New inhibitors of cancer cell proliferation with high selective activity and low toxicity have been identified which made it possible to propose them for preclinical studies. A method for evaluation of the substances toxicity using Paramecium has been developed which allows to accelerate and reduce the cost of biotesting. The mechanism of the substances effect on the cancer cells proliferation has been determined. The findings are of scientific interest and can be used for special training courses in Biopharmaceutical Chemistry, and Biochemistry.

Implementation of scientific results. A method for determination of direct toxicity of substances using Paramecium caudatum has been developed and patented. Two molecular inhibitors of cancer cell proliferation and one substance with antioxidant activity have been patented. Three innovations have been implemented as a result of modification and adaptation of methods for studying the biological activity of substances.