Samoylenko O. Molecular and biological mechanisms of the modification of ornithine decarboxylase functional state during tumor progression

Українська версія

Thesis for the degree of Candidate of Sciences (CSc)

State registration number

0425U000370

Thesis Registration Form

0425U000370.pdf

Applicant for

Specialization

  • 14.01.07 - Онкологія

12-11-2025

Specialized Academic Board

Д 26. 155. 01

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology National Academy of Sciences of Ukraine

Essay

The dissertation presents the results of scientific research demonstrating that tumor progression is a complex multifactorial process in which molecular and biochemical alterations play a critical role by driving proliferation, invasion, and metastasis. One of the central regulators of these processes is ornithine decarboxylase (ODC), an enzyme that catalyzes the first step of polyamine (PA) biosynthesis. Increased ODC activity is associated with enhanced tumor cell proliferation, activation of angiogenesis, and reduced efficacy of conventional chemotherapy, which substantiates its consideration as a promising therapeutic target. The study substantiates that synthetic ODC inhibitors – both direct (α-difluoromethylornithine, DFMO) and indirect (nor-arginine, MGBG, PMG) – can modulate the functional state of the enzyme directly and via epigenetic and signaling mechanisms. It was demonstrated that their combined use provides a more sustained antitumor activity compared to monotherapy, manifested by decreased ODC activity and content, inhibition of tumor growth, and reduction of metastatic potential. It was established that combined administration of DFMO and norarginine reduces ODC activity in LLC by 3.7-fold and ODC content in L1210 cells by 10-fold compared to control (p<0.05), significantly exceeding the effect of each inhibitor alone. The combination of DFMO with MGBG provided the most pronounced inhibition of L1210 cell growth (2.3-fold compared to control), while DFMO with nor-arginine consistently reduced LLC growth and metastasis volume. A strong positive correlation was revealed between ODC activity and tumor/metastasis volume in LLC (r=0.76–0.77), between ODC content and tumor volume in W-256 (r=0.82), and between ODC content and the number of tumor cells in ascitic fluid in L1210 and P388 (r=0.81 and r=0.65). Epigenetic analysis demonstrated that the use of inhibitor combinations alters methylation levels of odc1, oaz1, azin1, sat1, smox, and amd1. The most pronounced changes were observed with the combined use of DFMO and norarginine, which was accompanied by increased methylation of odc1, azin1, sat1, and amd1, as well as a decrease in ODC activity. Multivariate regression analysis identified methylation of odc1 and smox in LLC and odc1 and amd1 in L1210 as key epigenetic regulators of ODC functional state modification and the antitumor activity of the inhibitors. For the first time, it was demonstrated that combinations of synthetic ODC inhibitors modulate enzyme activity through combined effects on gene methylation, regulatory protein levels, and enzymatic degradation. Model-specific differences in the epigenetic regulation of ODC were identified between LLC and L1210. Practical significance. The obtained results provide a molecular basis for the development of new combination targeted therapy regimens using ODC inhibitors aimed at increasing treatment efficacy and reducing the risk of tumor resistance.

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Research papers

1. Самойленко, & Ганусевич, І. І. Епігенетичні механізми регуляції орнітиндекарбоксилази при лейкемії. Онкологія. 2025. Том. 27. № 1. С. 62–66 //Б

2. Samoilenko, О. А., Milinevska, O. A., Karnaushenko, O. V, Shlyakhovenko, V. A., & Zaletok, S. P. Effect of polyamine metabolism inhibitors on Lewis lung carcinoma growth and metastasis. Experimental Oncology. 2015. Vol. 37. No. 2. P. 151–153 // А

3. Shlyakhovenko, V., & Samoylenko, O. Photopolymerization with EDTA and Riboflavin for Proteins Analysis in Polyacrylamide Gel Electrophoresis. The Protein Journal. 2022. Vol. 41. No. 4. P. 438–443 // А

4. Zaletok, S., Gulua, L., Wicker, L., Shlyakhovenko, V., Gogol, S., Orlovsky, O., Karnaushenko, O., Verbinenko, A., Milinevska, V., Samoylenko, O., Todor, I., & Turmanidze, T. Green tea, red wine and lemon extracts reduce experimental tumor growth and cancer drug toxicity. Experimental Oncology. 2015. Vol. 37. No. 4. P. 262–-271 // А

5. Samoylenko, O., Zaletok, S., Orlovskiy, O., & Gogol, S. Additive antitumor effect of plant polyphenols and synthetic inhibitors of polyamines biosynthesis. Experimental Oncology. 2011. Vol. 33. No. 3. P. 186–189. Doi: http://dspace.nbuv.gov.ua/bitstream/handle/123456789/138637/10-Samoylenko.pdf?sequence=1 // А

6. Samoylenko ОА, O. О. А., Alexandrova, N. O., Ushenin Yu, V., & Zaletok, S. P. Development of a method to immobilize DNA on the «Biosuplar-5» SPR-spectrometer sensory chip for the study of polyamines effect on functional activity of transcription factors and expression of oncogenes dependent on them. Український Медичний Альманах. 2008. Vol. 11. No. 3. P. 25–35 // Б

7. Самойленко, О. А., Орловський, О. А., Кленов, О. О., Міліневська, В. О., Карнаушенко, О. В., Вербиненко, А. В., Шляховенко, В. О., & Залєток, С. П. Роль метилування генів ферментів метаболізму поліамінів в забезпеченні тривалості протипухлинної дії α-дифторметилорнітину. Збірник «Актуальні Проблеми Розвитку Світової Науки». 2017. Т. 1. С. 9–16 // Б

8. Залєток, С. П., Самойленко, О. А., Орловський, О. А., Міліневська, В. О., Кленов, О. О., Карнаушенко, О. В., Вербиненко, А. В., & Шляховенко, В. О. Вплив нораргініну (nor-Noha) на рівень метилювання генів, пов’язаних з метаболізмом поліамінів, і швидкість росту карциноми легені Lewis. Збірник «Актуальні проблеми розвитку світової науки». 2017. Т. 1. С. 16–23. // Б

9. Патент 45097 України на корисну модель МПК А61Р 43/00. Спосіб лікування злоякісних пухлин / С.П. Залєток, О.А. Самойленко, О.А. Орловський, О.О. Кленов, С.В. Гоголь, І.В. Малицька, В.В. Жиленко; заявник і патентовласник Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України; заявл. 25.05.2009; опубл. 26.10.2009. Бюл. № 20.

10. Міжнародній конференції «Пухлина та організм: сучасні аспекти старої проблеми» ( Київ, 21-24 вересня 2010)

11. Ukrainian-Swedish Workshop «New approaches in diagnostics and treatment of cancer» ( Київ, 13-14 червня 2011)

12. S. Zaletok, O. Samoylenko, L. Gulua, O. Orlovsky, S. Gogol, V. Milinevska, A. Verbinenko and O. Karnaushenko. Influence of nano green tea extract and nano composite of green tea extract and red wine lees on the growth of experimental tumors in animals. Thesis of Int. Conf. Exhib. Nutr. Sci. Ther. USA, Hilt. Philadelphia Cent. City, 27-29 August, 2012.

O. Samoylenko, S. Zaletok, O.Zhuravel, S. Gogol and L. Gulua. Molecular mechanisms of antitumor action of nano green tea extract and nanocomposite of green tea extract and red wine lees. Thesis of Int. Conf. Exhib. Nutr. Sci. Ther. USA, Hilt. Philadelphia Cent. City, 27-29 August, 2012

14. Е. Самойленко, С. Залеток, С. Гоголь, А. Орловский, Ю. Ушенин, Г. Бекетов, А. Самойлов, Р. Христосенко, Г. Дорожинский, Л. Гулуа. Определение содержания белков фактора транскрипции NF-κB и продуктов зависимых от него генов в экстрактах клеток животных с помощью поверхностного плазмонного резонанса. 5-та Міжнародна науково-технічна конференція «Сенсорна електроніка та мікросистемні технології» (СЕМСT-5), Одеса, 4-8 червня 2012 р

15. Залеток С., Гулуа Л., Шляховенко В., Орловский А., Гоголь С., Самойленко Е.,Кленов О., Карнаушенко Е., Вербиненко А., Милиневская В., Жиленкл В. Влияние наноэкстрактовзеленого чая и красного винограда на рост перевивных опухолей у экспериментальных животных. VII з’їзд онкологів і радіологів країн СДГ, Астана, 5-7 вересня 2012 р.

16. S.P. Zaletok, O.A. Samoylenko, O.V Zhuravel, O.A. Orlovsky. Effect of synthetic inhibitors of polyamine synthesis and plant polyphenols on the development of lymphocytic leukemia L1210 in mice, global methylation of DNA, methylation of ODC gene and polyamines contents in tumor cells. Thesis of International Congress on «Polyamines: Biological and Clinical Perspectives», Istanbul, 2-7 September 2012.

17. S. Zaletok, O. Samoylenko, O. Zhuravel, L. Gulua, V. Chekhun. Anticancer effect of green tea nanoextract is associated with modifications in methylation of genes involved in proliferation and apoptosis. Thesis of 11th Int. Symp. (TAT 2013), Paris, 4–6 March 2013.

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